Bicyclic heterocycles as HIV integrase inhibitors

ABSTRACT

The invention encompasses a series cyclic bicyclic pyrimidinone compounds of Formula I which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.Nos. 60/603,371 filed Aug. 20, 2004 and 60/575,513 filed May 28, 2004.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) has been identified as theetiological agent responsible for acquired immune deficiency syndrome(AIDS), a fatal disease characterized by destruction of the immunesystem and the inability to fight off life threatening opportunisticinfections. Recent statistics (UNAIDS: Report on the Global HIV/AIDSEpidemic, December 1998), indicate that as many as 33 million peopleworldwide are infected with the virus. In addition to the large numberof individuals already infected, the virus continues to spread.Estimates from 1998 point to close to 6 million new infections in thatyear alone. In the same year there were approximately 2.5 million deathsassociated with HIV and AIDS.

There are currently a number of antiviral drugs available to combat theinfection. These drugs can be divided into three classes based on theviral protein they target and their mode of action. In particular,saquinavir, indinavir, ritonavir, nelfinavir and amprenavir arecompetitive inhibitors of the aspartyl protease expressed by HIV.Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavirare nucleoside reverse transcriptase inhibitors that behave as substratemimics to halt viral cDNA synthesis. The non-nucleoside reversetranscriptase inhibitors, nevaripine, delavirdine and efavirenz inhibitthe synthesis of viral cDNA via a non-competitive (or uncompetitive)mechanism. Used alone these drugs are effective in reducing viralreplication. The effect is only temporary as the virus readily developsresistance to all known agents. However, combination therapy has provenvery effective at both reducing virus and suppressing the emergence ofresistance in a number of patients. In the US, where combination therapyis widely available, the number of HIV-related deaths has declined(Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.;Further, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J.Med. 1998, 338, 853–860).

Unfortunately, not all patients are responsive and a large number failthis therapy. In fact, approximately 30–50% of patients ultimately failcombination therapy. Treatment failure in most cases is caused by theemergence of viral resistance. Viral resistance in turn is caused by therapid turnover of HIV-1 during the course of infection combined with ahigh viral mutation rate. Under these circumstances incomplete viralsuppression caused by insufficient drug potency, poor compliance to thecomplicated drug regiment as well as intrinsic pharmacological barriersto exposure provides fertile ground for resistance to emerge. Moredisturbing are recent findings which suggest that low-level replicationcontinues even when viral plasma levels have dropped below detectablelevels (<50 copies/ml) (Carpenter, C. C.; Cooper, D. A.; Fischl, M. A.;Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.; Jacobsen,D. M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D. D.; Saag, M. S.;Schechter, M.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.;Volberding, P. A. JAMA 2000, 283, 381–390). Clearly there is a need fornew antiviral agents, preferably targeting other viral enzymes to reducethe rate of resistance and suppress viral replication even further.

HIV expresses three enzymes, reverse transcriptase, an aspartylprotease, and integrase. All three are targets for treating AIDS and HIVinfection. HIV integrase catalyzes insertion of the viral cDNA into thehost cell genome, which is a critical step in the viral life cycle. HIVintegrase inhibitors belonging to a class of diketo acid compoundsprevented viral integration and inhibited HIV-1 replication in cells(Hazuda et al. Science 2000, 287, 646). And recently, HIV integraseinhibitors have been accepted into clinical trials for treating AIDS andHIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Paisand Burke Drugs Fut. 2002, 27, 1101).

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I, includingpharmaceutically acceptable salts and solvates, their pharmaceuticalcompositions, and their use in inhibiting HIV integrase and treatingthose infected with HIV or AIDS.

One aspect of the invention are compounds of Formula I

wherein:

-   R¹ is C₁₋₆(Ar¹)alkyl, C₁₋₆(Ar¹)(CON(R⁸)(R⁹))alkyl,    C₁₋₆(Ar¹)(CO₂R¹⁴)alkyl, C₁₋₆(Ar¹)hydroxyalkyl, or C₁₋₆(Ar¹)oxyalkyl;-   R² is hydrogen, C₁₋₆alkyl, or OR¹⁴;-   R³ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₅₋₇cycloalkenyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆alkylthio,    C₁₋₆haloalkoxy, N(R⁸)(R⁹), NHAr², N(R⁶)SO₂R⁷, N(R⁶)COR⁷, N(R⁶)CO₂R⁷,    OCOR⁷, OCO₂R⁷, OCON(R⁸)(R⁹), OCH₂CO₂R⁷, OCH₂CON(R⁸)(R⁹), COR⁶,    CO₂R⁶, CON(R⁸)(R⁹), SOR⁷, S(═N)R⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), PO(OR⁶)₂,    C₂₋₄(R¹²)alkynyl, R¹³, Ar², or Ar³;-   R⁴ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆haloalkyl, C₁₋₆haloalkoxy, or N(R⁶)(R⁶);-   R⁵ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆    haloalkyl, C₁₋₆haloalkoxy, or N(R⁶)(R⁶);-   R⁶ is hydrogen, C₁₋₆alkyl, or C₃₋₇cycloalkyl;-   R⁷ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   R⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl    or C₁₋₆(C₁₋₆dialkylamino)alkyl;-   R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl    or C₁₋₆(C₁₋₆dialkylamino)alkyl; or-   N(R⁸)(R⁹) taken together is azetidinyl, pyrrolidinyl,    (R¹⁰)-piperidinyl, N-(R¹¹)-piperazinyl, morpholinyl,    thiomorpholinyl, or dioxothiazinyl;-   R¹⁰ is hydrogen, C₁₋₆alkyl, or C₁₋₆hydroxyalkyl;-   R¹¹ is hydrogen, C₁₋₆alkyl, C₃₋₇cyclolkyl, COR⁶, or CO₂R⁶;-   R¹² is hydrogen, hydroxy, N(R⁶)(R⁶), SO₂R⁷, OSO₂R⁷, or    dioxothiazinyl;-   R¹³ is azetidinonyl, pyrrolidinonyl, valerolactamyl, caprolactamyl,    maleimido, oxazolidonyl, or dioxothiazinyl, and is substituted with    0–1 substituents selected from the group consisting of    hydroxymethyl, acetoxymethyl, and aminomethyl;-   R¹⁴ is hydrogen or C₁₋₆alkyl;

-   Ar² is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,    imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl,    thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl,    hydroxypyridinyl, quinolinyl, isoquinolinyl, or indolyl, and is    substituted with 0–2 substituents selected from the group consisting    of halo, cyano, benzyl, C₁₋₆alkyl, C₁₋₆alkoxy, N(R⁸)(R⁹),    CON(R⁸)(R⁹), CO₂R⁶, CONHSO₂N(R⁶)(R⁶), CONHSO₂N(R⁶)(phenyl), and    CONHSO₂N(R⁶)(halophenyl);-   Ar³ is phenyl substituted with 0–2 substituents selected from the    group consisting of halo, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,    (C₁₋₆alkoxy)methyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, N(R⁸)(R⁹),    CON(R⁶)(R⁶), and CH₂N(R⁸)(R⁹), or is dioxolanylphenyl; and-   X—Y—Z is C(R¹⁴)₂OC(R¹⁴)₂, C(R¹⁴)₂OC(R¹⁴)₂C(R¹⁴)₂, or    C(R¹⁴)₂OC(R¹⁴)₂C(R¹⁴)₂C(R¹⁴)₂;    or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a compound of Formula I where R¹ isC₁₋₆(Ar¹)alkyl.

Another aspect of the invention is a compound of Formula I where R¹ is

Another aspect of the invention is a compound of Formula I where R¹ is

Another aspect of the invention is a compound of Formula I where R² ishydrogen.

Another aspect of the invention is a compound of Formula I where R³ ishydrogen, halo, N(R⁸)(R⁹), N(R⁶)COR⁷, OCON(R⁸)(R⁹), CON(R⁸)(R⁹), SOR⁷,SO₂R⁷, SO₂N(R⁶)(R⁶), PO(OR⁶)₂, R¹³, or Ar².

Another aspect of the invention is a compound of Formula I where X—Y—Zis C(R¹⁴)₂OCH₂, C(R¹⁴)₂OCH₂CH₂, or C(R¹⁴)₂OCH₂CH₂CH₂.

Another aspect of the invention is a compound of Formula I where X—Y—Zis CH₂OCH₂, C(CH₃)HOCH₂, C(CH₃)₂OCH₂, CH₂OCH₂CH₂, C(CH₃)HOCH₂CH₂,C(CH₃)₂OCH₂CH₂, CH₂OCH₂CH₂CH₂, C(CH₃)HOCH₂CH₂CH₂, or C(CH₃)₂OCH₂CH₂CH₂.

For a compound of Formula I, any scope of R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, Ar¹, Ar², Ar³, and X—Y—Z can be usedindependently with any scope of any other substituent.

“Alkyl,” “alkoxy,” “hydroxyalkyl,” and related terms with an alkylmoiety include straight and branched configurations. A term such as“C₁₋₆(R)alkyl” means a straight or branched alkyl group of one to sixcarbons substituted with the substituent R. “Haloalkyl” and “halophenyl”include all permutations of halogenated alkyl or phenyl groups, frommonohalo to perhalo. “Aryl” means an aromatic ring system and includescarbocyclic and heterocyclic systems. Some substituents are divalent,such as X—Y—Z. Asymmetric divalent substituents may be attached ineither of the two configurations.

“C₁₋₆(Ar¹)oxyalkyl” means Ar¹ is attached at the oxygen.

“Dioxolanyphenyl” means

“Dioxothiazinyl” means

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

The invention also includes all solvated forms of the compounds,particularly hydrates. Solvates do not contribute significantly to thephysiological activity or toxicity of the compounds and as such functionas pharmacological equivalents. Solvates may form in stoichiometricamounts or may form from adventitious solvent or a combination of both.One type of solvate is hydrate, and some hydrated forms includemonohydrate, hemihydrate, and dihydrate.

Some of the compounds of the invention exist in stereoisomeric forms.The invention includes all stereoisomeric forms of the compoundsincluding enantiomers and diastereromers. An example of enantiomers isshown below. Methods of making and separating stereoisomers are known inthe art.

The invention includes all tautomeric forms of the compounds. An exampleof a tautomeric pair is shown below.

Synthetic Methods

The compounds of this invention can be made by various methods known inthe art including those of the following schemes and in the specificembodiments section. The variables shown in the synthetic schemes aredistinct from and should not be confused with the variables in theclaims or the rest of the specification. The variables in the schemesare meant only to illustrate how to make some of the compounds of thisinvention.

Some compounds can be synthesized from an appropriately substitutedheterocycle I-1 according to Scheme I, where R_(a) and P can serve asprotecting groups (see Greene, T. W. and Wutz, P. G. M. ProtectiveGroups in Organic Synthesis, Second Edition, 1991, John Wiley and Sons,New York). When P is benzyl or substituted benzyl it can be removed byhydrogenolysis (H₂-Pd/C) or acid hydrolysis (trifluoroacetic acid) toyield intermediate I-2. I-2 can be transaminated to 1–4 by reaction withamine 1–3. In a number of cases this reaction can be carried out byheating 1–3 and I-2 together in the presence of base. Alternatively,standard amide coupling reagents can be used to effect the formation ofthe amide bond. When R_(a) is a lower alkyl group, R_(a) can be removedunder ester hydrolysis conditions, such as treatment with NaOH, LiOH, orKOH to deliver the corresponding carboxylic acid I-5. Alternatively,R_(a) can be removed by nucleophilic displacement using NaI. When R_(a)is benzyl and substituted benzyl, R_(a) can be removed byhydrogenolysis. Intermediate I-5 can be coupled using amide bond formingreagents such as BOP, DCC, EDCI, PyBrop, PyBop or other reagents (seeMarch, J. Advanced Organic Chemistry, Fourth Edition 1992 John Wiley &Sons, New York). The resulting intermediate I-6 can be deprotected asdescribed for intermediate I-1.

In Scheme II, intermediate II-3 can be prepared using methods similar tothose described in Sunderland, J. S.; Botta, M.; Aime, S.; Raymond, K.N. Inorg. Chem. (2001), 40, 6756–6756, where II-1 and II-2 arecondensed, to provide intermediate II-3. This reaction is usuallyconducted in the presence of a base such as sodium hydride (NaH), sodiumethoxide (EtONa) or lithium hexamethyldisilazide (LiHMDS). Using themethods described in the reference, II-3 can be condensed with anappropriately substituted amidine II-4 to form II-5. Substituent B canbe a leaving group, such as—halo (Cl, Br or I) or can be converted to aleaving group under appropriate conditions such as by forming thecorresponding methylsulfonate ester. When substituent B is a methylsulphide group it can be treated with iodomethane to form adimethylsulfonium intermediate which is activated towards nucleophilicattack to effect ring closure.

In Scheme III, intermediate II-3 can be condensed with a cyclic-amidineto yield intermediate I-1. Intermediate III-1 can be prepared usingknown methods (see Patai, S. and Rappoport, Z. The Chemistry of Amidinesand Imidates, Volume 2, 1991, John Wiley & Sons, New York).

In Scheme IV, nitrile IV-1, possessing a potential leaving group B, canbe reacted with hydroxylamine to form intermediate IV-2. Thisintermediate can be reacted with a suitably protected alkyne to formIV-3 which can rearrange to from intermediate IV-4 according toliterature methods (Culbertson, T. P. Journal of Heterocyclic Chemistry,1979, 16, 1423–1424).

As shown in Scheme V, 2-(methylthio)ethanol can be alkylated with anappropriate α-haloacetic acid (V-1) wherein X is a leaving group such asCl, Br, OTs, OMs or OTf, to deliver intermediate V-2. Following this,the carboxylic acid can be transformed to the corresponding amidinederivative using known synthetic methods (Geilen et al. TetrahedronLetters 2002, 43, 419–421). As described in the above, the amidine canfurther be reacted with intermediate V-5, in the presence of a base (forexample, sodium ethoxide) affording intermediate V-6. Methylation of thesulphide ether can be accomplished by treating V-6 with iodomethane andthe resulting sulfonium derivative (V-7) treated with base to form thebicyclic template V-8. This intermediate can be used in the synthesis offinal compounds using methods described in Scheme I.

In Scheme VI, 3-methylthiopropanal is converted to dioxolane VI-1 usingwell known chemistry. Treatment with trimethylsilylcyanide (TMSCN), inthe presence of zinc iodide (ZnI₂) produces intermediate VI-2. Reactionwith ammonia provides amidine VI-3 which is used in the synthesis ofpyrimidinone VI-4 according to the methods described in the previousschemes. Subsequent treatment with CH₃SO₂Cl and triethylamine (Et₃N)results in the corresponding bicyclic intermediate VI-5. Completion ofthe synthesis can be carried out as illustrated in Scheme I.

Another method is illustrated in Scheme VII. This synthetic path beginswith an appropriately substituted ketone which can be transformed to thecorresponding nitrile intermediate VII-1. This in turn can be reactedwith 2-chloroethanol to produce compound VII-2, which can be reactedwith hydroxylamine and an acetylene dicarboxylate ester to yieldintermediate VII-4. Heating of the intermediate can yield intermediateVII-5. Synthesis of the corresponding amide derivatives can beaccomplished according to Scheme I.

In Scheme VIII, benzylation of the hydroxyl group of VII-5, as a meansof functional group protection, can be achieved using benzyl bromideunder basic conditions (for example, K₂CO₃ or NaH). Saponification ofthe ester group of VIII-1 can provide VIII-2 which can be coupled withappropriately substituted amines (R¹R²NH) using well known amide bondforming reagents, such asbenzotriazole-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP) or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU). Alternatively, the corresponding acidchloride can be formed, by treatment with oxalyl chloride, and reactedwith an appropriate amine to form the amide bond. Removal of the benzylgroup can be accomplished under a variety of conditions includingtreatment with CF₃CO₂H or H₂ (Pd—C).

In yet another method, some compounds of this invention can besynthesized according to Scheme IX. In Scheme IX, pyrimidinone IX-3, canbe produced using methods similar to those described in the previousschemes. This intermediate can be carried on to the final productaccording to a variety of paths. In one, the hydroxyl group can bebenzoylated to provide intermediate IX-4 which can be further treatedwith K₂CO₃ to effect ring closure to form the bicyclic template IX-5.Alternatively, direct treatment of IX-3 with K₂CO₃ can provideintermediate IX-6. Intermediates IX-5, an IX-6 can be used in thesynthesis the final products using the methods described in Scheme I.

In Scheme X, IX-3 can be used to synthesize the benzylated intermediateX-1. This intermediate can be carried on to final product using methodsanalogous to those described in Scheme VIII.

The synthesis of (2-(aminomethyl)-5-fluorophenyl)(morpholino)methanonehydrochloride is illustrated in Scheme XI.

In Scheme XII, bicyclic intermediate XII-1, prepared according to themethods described above, can be saponified using well known methods. Theresulting carboxylic acid, XII-3, can then be coupled to amine XII-2using standard amide bond forming reagents and methods. Removal of thebenzyl group, by hydrogenolysis or acid mediated hydrolysis provides thefinal products.

An alternative route to compounds similar to those presented in SchemeXII is given in Scheme XIII. In this scheme the ester group of XIII-1can be hydrolyzed and the resulting carboxylic acid coupled to methyl2-(aminomethyl)-5-fluorobenzoate. A second hydrolysis reaction canproduce XIII-4 which can be coupled with a second amine. This isfollowed by removal of the benzyl group to provide the final products.

In yet another method, Scheme XIV illustrates the synthesis ofsulfonamide containing examples, starting from5-fluoro-2-methylbenzen-1-sulfonlyl chloride.

Further illustration of methods used for the synthesis of certaincompounds of the invention is shown in Scheme XV. Methylation of5-(2-bromo-5-fluorophenyl)-1H-tetrazole can yield a mixture of XV-1 andXV-2 that can be separated and each of the compounds carried on to thecorresponding final products.

Some diazarine and diaziradine analogues can be synthesized according toScheme XVI.

Some examples of the invention can be synthesized according to themethods illustrated in Schemes XVII–XX.

In Scheme XXI, 2-bromo-benzonitrile or 2-bromo-4-fluoro-benzonitrile canbe coupled with an appropriate amide to provide XXI-1. Reduction of thenitrile group provides XXI-2 which can be used in the synthesis of thefinal product according to the methods described in the previousschemes. In most cases, compound XXI-1 need not be isolated but can becarried directly into the coupling reaction to form XXI-3.

The examples and methods shown in Scheme XXII are similar to thosedepicted in Scheme XXI.

Schemes XXIV and XXV further illustrate methods useful for the synthesisof some compounds of the invention.

In Scheme XXVI, intermediate XXVI-1 can be used to synthesizeintermediates XXVI-2 via palladium catalyzed coupling. Theseintermediates can be further modified to provide some of the compoundsof this invention.

Another method is illustrated in Scheme XXVII.

In Scheme XXVIII, compound XXVIII-1 can be converted to thecorresponding methylsulfonate derivate, XXVIII-2, which can besubsequently treated with sodium azide to yield XXVIII-3. This compoundin turn can serve as an intermediate for further transformation asillustrated in the scheme.

Certain examples of the current invention can be synthesized accordingto the methods illustrated in Schemes XXIX–XXXVIII.

Biological Methods

HIV-Integrase Inhibition Activity. To evaluate in-vitro activity againstHIV-integrase, 5 pmole of biotin labeled substrate DNA was bound to 100μg of Streptavidin coated PVT SPA beads (Amersham Pharmacia Biotech).Recombinant integrase (0.26 ng) was incubated with the beads for 90 minat 37° C. Unbound enzyme was removed by washing the complex followed byaddition of inhibitors and 0.1 fmol of P33 labeled target DNA. Thereaction was stopped by adding EDTA to a final concentration of 10 mM.Samples were counted in TopCountNXT (Packard) and the CPM was used as ameasure of integration. The reaction condition was as described in A.Engelman and R. Craigie, J. Virol. 69, 5908–5911 (1995). The sequencesof substrate and target DNA were described in Nucleic Acid Research22,1121–1122 (1994). Results are shown in the Table 1. Activity equal toA refers to a compound having IC₅₀=0.002 to 0.10 μM while B and C denotecompounds having IC₅₀=0.1 to 1.0 μM and IC₅₀≧1.0 μM respectively.

TABLE 1 Example Activity 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22 B 23 A 24 B 25 B 26A 27 A 28 A 29 A 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 A 38 A 39 A 40 A41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 A 54 A 55A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 C 84A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 A 96 A 97 A 98 A99 A 100 A 101 A 102 A 103 A 104 B 105 A 106 A 107 A 108 A 109 A 110 A111 A 112 A 113 A 114 A 115 A 116 A 117 A 118 A 119 A 120 A 121 A 122 A123 A 124 A 125 A 126 A 127 A 128 A 129 A 130 A 131 B 132 A 133 B 134 A135 A 136 A 137 A 138 A 139 A 140 A 141 A 142 A 143 A 144 B 145 C 146 A147 A 148 B 149 A 150 A 151 A 152 A 153 A 154 A 155 A 156 A 157 A 158 A159 B 160 A 161 A 162 A 163 A 164 A 165 A 166 B 167 A 168 A 169 A 170 A171 A 172 A 173 A 174 A 175 A 176 A 177 A 178 A 179 A 180 A 181 A 187 A188 A 189 A 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 A200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 A 211 A212 A 213 A 214 C 215 A 216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A224 A 225 A 226 A 227 A 228 A 229 A 230 A 231 A 232 A 233 A 234 A 235 A236 A 237 A 238 A 239 A 240 A 241 A 242 A 243 A 244 A 245 A 246 A 247 A248 A 249 A 250 A 251 A 252 B 253 C 254 A 255 A 256 B 257 A 258 A 259 A260 A 261 A 262 A 263 A 264 A 265 A 266 A 267 A 268 A 269 A 270 A 271 A272 A 273 A 274 A 275 A 276 A 277 A 278 A 279 A 280 A 281 A 282 A

Inhibition of HIV replication. A recombinant NL-Rluc virus wasconstructed in which a section of the nef gene from NL4-3 was replacedwith the Renilla Luciferase gene. The NL-RLuc virus was prepared byco-transfection of two plasmids, pNLRLuc and pVSVenv. The pNLRLuccontains the NL-Rluc DNA cloned into pUC18 at the PvuII site, while thepVSVenv contains the gene for VSV G protein linked to an LTR promoter.Transfections were performed at a 1:3 ratio of pNLRLuc to pVSVenv on293T cells using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad,Calif.) according to manufactures instruction, and the pseudotype virusgenerated was titered in MT-2 cells.

Susceptibility of viruses to compounds was determined by incubation inthe presence of serial dilutions of the compound. The 50% effectiveconcentration (EC₅₀) was calculated by using the exponential form of themedian effect equation where (Fa)=1/[1+(ED₅₀/drug conc.)^(m)] (Johnson VA, Byington R T. Infectivity Assay. In Techniques in HIV Research. ed.Aldovini A, Walker B D. 71–76. New York: Stockton Press, 1990). Theanti-viral activity of compounds was evaluated under three serumconditions, 10% FBS, 15 mg/ml human serum albumin/10% FBS or 40% humanserum/5% FBS, and the results from at least 2 experiments were used tocalculate the EC₅₀ values. Results are shown in the Table 2. Activityequal to A refers to a compound having EC₅₀=0.003 to 0.10 μM while B andC denote compounds with EC₅₀0.1 to 1.0 μM and EC₅₀≧1.0 μM respectively.

TABLE 2 Example Activity 1 B 2 A 3 C 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22 B 23 A 24 C 25 C 26A 27 A 28 B 29 A 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 B 38 A 39 A 40 A41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 B 49 A 50 A 51 A 52 A 53 B 54 A 55A 56 A 57 A 58 A 59 B 60 A 61 B 62 A 63 A 64 C 65 A 66 B 67 A 68 C 69 A70 B 71 B 72 B 73 A 74 A 75 A 76 B 77 A 78 A 79 B 80 B 81 A 82 A 83 C 84A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 A 96 A 97 A 98 A99 A 100 A 101 A 102 A 103 B 104 B 105 A 106 A 107 A 108 A 109 A 110 A111 A 113 A 114 A 115 A 116 A 117 A 118 A 119 A 120 A 121 A 122 A 123 A124 A 125 A 126 A 127 A 128 A 129 A 130 A 132 A 133 B 134 A 135 A 136 A137 B 138 A 139 A 140 A 141 C 142 B 144 C 146 A 147 B 148 B 149 B 150 B151 B 152 B 153 B 154 B 155 B 156 B 157 A 158 A 159 A 160 B 161 B 162 A163 B 164 B 165 A 166 C 167 B 168 A 169 A 170 A 171 B 172 B 173 A 174 A175 B 176 A 177 A 178 A 179 B 180 C 181 A 187 B 188 B 189 A 190 A 191 B192 B 193 C 194 B 195 B 196 A 197 C 198 B 199 B 200 A 201 B 202 A 203 A204 A 205 A 206 A 207 A 208 A 209 B 210 A 211 A 212 A 213 A 214 B 215 A216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A 224 B 225 A 226 A 227 B228 B 229 A 230 A 231 A 232 A 233 A 234 A 235 A 236 B 237 A 238 A 239 A240 A 241 A 242 A 243 A 244 A 245 A 246 A 247 A 248 A 249 A 250 A 251 A252 C 253 C 254 A 255 A 256 B 257 A 258 A 259 A 260 A 262 A 263 B 265 B266 A 267 A 268 A 270 A 273 B 279 A 281 A 282 A

Combination Studies

Example 19 demonstrated synergistic or additive-synergistic HIVantiviral activity when used in conjunction with a variety of otherantiviral agents, as described below.

Virus and cell lines. The T-cell line, MT-2, was obtained through theAIDS Research and Reference Reagent Program. MT-2 cells weresub-cultured twice a week in RPMI 1640 medium supplemented with 10%fetal bovine serum, 2 mM L-glutamine, and 10 mM HEPES buffer pH 7.5. TheHIV-1 303B virus is a molecular clone derived from the NL4-3 strain ofHIV-1 that was obtained from the NIH AIDS Research and Reference ReagentProgram. For combinations with enfuvirtide, the NL36G virus was used.This NL4-3 derivative has the naturally occurring enfuvirtide resistancemutation in gp41 (36D) changed to a sensitive phenotype (D36G). Virusstocks were made by transfecting 293T cells with a proviral DNA cloneusing LipofectAMINE PLUS (Invitrogen), according to the manufacturer'sinstructions. Three days post-transfection, virus was harvested andpassaged once in MT-2 cells before titration in MT-2 cells.

Chemicals. Example 19, atazanavir, didanosine, stavudine, efavirenz, andenfuvirtide (T-20) were synthesized by Bristol-Myers Squibb usingpublished or known reactions. Amprenavir, indinavir, nelfinavir,nevirapine, lopinavir, lamivudine, ritonavir, tenofovir, saquinavir,delavirdine and abacavir were extracted from commercial formulations ofthe prescribed drugs and purified using published or common techniques.Tenofovir was tested as tenofovir disopoxil fumerate. Zidovudine andzalcitabine were purchased from Sigma, and emtricitabine from MoravekBiochemicals.

Drug Susceptibility and Cytotoxicity Assays. For drug susceptibilityassays, MT-2 cells were infected with HIV-1 303B (or NL36G), at an MOIof 0.001, and seeded into 96-well microtiter plates (2.5×10⁵ cells/ml)containing serial dilutions of test compounds. The drug combinationswere set up using ratios of the two drugs of 1:1, 1:2.5 and 2.5:1 timesthe EC₅₀ value determined for each drug in prior experiments. Each drugratio consisted of an array of 3-fold serial dilutions, and wasperformed with eight or more replicas on separate multi-well plates. HIVinfected cells were incubated at 37° C. in 5% CO₂, and on day fivepost-infection, the extent of virus replication was measured bydetermining cell viability using the CellTiter 96 AqueousNon-Radioactive Cell Proliferation Assay (Promega). Maximal cellprotection was typically seen in samples treated with the highest drugconcentration. In the cell viability assay, the tetrazolium compound MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2–4-sulphophenyl-2H-tetrazolium)is added to cells, whereby enzymes in metabolically active cells convertit into a colored formazan product, which is quantitated by readingabsorbance at 490 nm. Cytotoxicity assays were performed in parallelwith the combination experiments. Here, uninfected cells were exposed tothe same drug combinations, and assayed after five days for cellviability using the MTS assay.

Analysis of Drug Combination Effects. For determination of combinationindex (CI) values, drugs were diluted in a fixed ratio and multipleratios were analyzed. The drug serial dilutions spanned a range ofconcentrations near the EC₅₀ value of each compound, so that equivalentantiviral activities could be compared. The normalized responses fromeach therapy are fit to the four-parameter logistic model with a commonminimum and maximum across all therapies. Conceptually, this equationcan be written as

${{Fa}_{i} = {A + \frac{D - A}{1 + \left( \frac{C_{1}^{I_{1}}C_{2}^{I_{2}}C_{3}^{I_{3}}C_{4}^{I_{4}}C_{5}^{I_{5}}}{{concentration}_{i}} \right)^{B_{1}^{I_{1}}B_{2}^{I_{2}}B_{3}^{I_{3}}B_{4}^{I_{4}}B_{5}^{I_{5}}}}}},{where}$$\begin{matrix}{I_{j} = \left\{ {\begin{matrix}1 & {{{if}\mspace{14mu}{therapy}} = j} \\0 & {otherwise}\end{matrix}\mspace{14mu}{for}} \right.} \\{{j = 1},2,3,4,{{or}\mspace{14mu} 5.}}\end{matrix}$

In this equation, Fa stands for “fraction affected,” and represents thefraction of the viral load that has been inactivated. For example, Fa of0.75 indicates that viral replication had been inhibited by 75%,relative to the no-drug controls. The EC₅₀, represented by the C_(i) inthe above equation, is the drug concentration that is expected to reducethe amount of virus by 50%, and the B_(i) are the parameters thatreflects the slope of the concentration-response curve. For this assay,A is the bottom plateau common to all curves, D is the common topplateau, B_(j) is the “slope” parameter for the jth therapy, and C_(j)is the concentration that produces an effect equal to the average of Aand D for the jth therapy. Therapies 1 and 2 correspond to monotherapies 1 and 2, respectively. Therapies 3, 4, and 5 correspond to thethree combination therapies. EC₅₀ values for each drug were determinedfrom the single drug experiments, using the above equation. The equationwas fit using a nonlinear regression routine (Proc Nlin) in PC SASversion 8.2 (SAS Institute Inc.).

To assess antiviral effects of different drug combination treatments,combination indices (CIs) were calculated according to Chou and Rideout.The combination index was computed as

${CI} = {\frac{\lbrack D\rbrack_{1}}{\lbrack{Dm}\rbrack_{1}} + \frac{\lbrack D\rbrack_{2}}{\lbrack{Dm}\rbrack_{2}}}$

In this equation [Dm]₁ and [Dm]₂ are the concentrations of drugs thatwould individually produce a specific level of effect, while [D]₁ and[D]₂ are the concentrations of drugs in combination that would producethe same level of effect.

Theoretically, additivity is implied if the CI is equal to one, synergyif the CI is less than one, and antagonism if the CI is greater thanone. However, extensive experience with combination studies indicatesthat there are inherent laboratory variables that must be taken intoaccount in interpreting the CIs. At best, a range can be constructedthat contains the likely values for the CI, given the noise in the data.In this report, these ranges are reported in parentheses next to eachpoint estimate of the CI. For example, when a CI of “0.52 (0.36, 0.69)”is reported this means that the best estimate of the CI is 0.52, but dueto noise in the data, values from 0.36 to 0.69 are also reasonablevalues for the CI. This range, 0.36 to 0.69 falls entirely below thevalue of 1.0, and hence all likely values for the CI are less than 1.0.Therefore, synergistic behavior can be inferred for this combination. Ifthe range fell entirely above 1.0, we would infer antagonistic behavior.If the range were to include 1.0, we would infer additivity.

In carrying out the combination experiments, the EC₅₀ for Example 19 andeach comparator compound was determined during the course of each study,and used in the subsequent data analysis. The determined values areconsistent with previously published data and are shown in Table 3.

TABLE 3 Anti-HIV Activity of Compounds in Two-Drug Combination StudiesHighest Drug Compound EC₅₀ (μM) Concentration (μM) Example19 0.022 2.5Zidovudine 0.012 2.5 Didanosine 10.7 100 Stavudine 0.241 15 Lamivudine0.203 15 Abacavir 1.04 30 Tenofovir 0.018 2.5 Emtricitabine 0.053 20Zalcitabine 0.124 10 Efavirenz 0.0016 0.2 Nevirapine 0.095 5 Delavirdine0.043 5 Ritonavir 0.048 2.5 Indinavir 0.026 2.5 Nelfinavir 0.022 2.5Saquinavir 0.011 2.5 Amprenavir 0.062 2.5 Atazanavir 0.010 1 Lopinavir0.017 2.5 Enfuvirtide 0.061 2.2

Two-Drug Combinations of Example 19 with Nucleoside ReverseTranscriptase Inhibitors. Eight nucleoside RT inhibitors (didanosine,stavudine, zidovudine, lamivudine, abacavir, zalcitabine, emtricitibineand the nucleoside phosphonate, tenofovir) were combined with Example 19at a range of concentrations near the EC₅₀ value of each compound, sothat equivalent antiviral activities could be compared. All estimateswere computed using SAS Proc NLIN, and a two-parameter logistic. Data ispresented in Table 4 as the combination indices and the asymptoticconfidence intervals for RT inhibitors at different molar ratios.

Four nucleoside RT inhibitors; didanosine, stavudine, abacavir andemtricitibine, show synergistic antiviral effects in combination withExample 19 at all effective levels and all molar ratios. The other fourRT inhibitors: zidovudine, lamivudine, tenofovir and zalcitabine allhave combination indices suggestive of synergistic behavior with Example19. However, the upper ranges of the confidence intervals for some ofthe effective levels are greater than 1, so the overall effects of thesecompounds with Example 19 are classified as synergistic to additive. Nosignificant antagonism of anti-HIV activity is observed. No enhancedcytotoxicity was encountered at the highest concentrations tested withany of the drug combinations, as measured by the XTT reduction assay.

TABLE 4 Two-Drug Combinations using Example 19 and Nucleoside ReverseTranscriptase Inhibitors. Combination Indices at % HIV Inhibition^(b)Molar Ratio (Confidence Interval) (EC₅₀ Ratio)^(a) 50% 75% 90%Zidovudine   1:1 (1:1) 0.59 (0.49, 0.69) 0.56 (0.41, 0.70) 0.54 (0.36,0.70)   2:5 (1:2.5) 0.65 (0.56, 0.75) 0.73 (0.59, 0.86) 0.81 (0.57,1.06)   5:2 (2.5:1) 0.72 (0.61, 0.83) 0.83 (0.64, 1.02) 0.96 (0.63,1.30) Didanosine 1:1000 (1:1) 0.58 (0.53, 0.63) 0.47 (0.35, 0.60) 0.39(0.22, 0.56) 1:2500 (1:2.5) 0.56 (0.51, 0.62) 0.46 (0.40, 0.52) 0.38(0.32, 0.44)  1:400 (2.5:1) 0.50 (0.46, 0.54) 0.49 (0.44, 0.53) 0.48(0.42, 0.54) Stavudine   1:6 (1:1) 0.52 (0.43, 0.61) 0.46 (0.36, 0.56)0.42 (0.26, 0.57)  1:15 (1:2.5) 0.60 (0.48, 0.71) 0.60 (0.46, 0.74) 0.61(0.40, 0.83)  5:12 (2.5:1) 0.70 (0.57, 0.84) 0.63 (0.48, 0.79) 0.58(0.37, 0.81) Lamivudine   1:6 (1:1) 0.80 (0.63, 0.98) 0.80 (0.55, 1.05)0.81 (0.42, 1.21)  1:15 (1:2.5) 1.09 (0.88, 1.31) 1.00 (0.72, 1.27) 0.92(0.52, 1.33)  5:12 (2.5:1) 0.94 (0.80, 1.08) 0.84 (0.65, 1.03) 0.75(0.49, 1.02) Abacavir  1:30 (1:1) 0.68 (0.59, 0.76) 0.67 (0.56, 0.79)0.67 (0.49, 0.84)  1:75 (1:2.5) 0.87 (0.77, 0.97) 0.74 (0.63, 0.85) 0.63(0.50, 0.77)  1:12 (2.5:1) 0.86 (0.76, 0.96) 0.82 (0.68, 0.96) 0.79(0.58, 0.99) Tenofovir   1:1 (1:1) 0.66 (0.57, 0.75) 0.54 (0.45, 0.62)0.43 (0.33, 0.53)   2:5 (1:2.5) 0.68 (0.59, 0.77) 0.60 (0.48, 0.72) 0.52(0.36, 0.69)   5:2 (2.5:1) 0.90 (0.77, 1.04) 0.84 (0.67, 1.01) 0.79(0.55, 1.03) Zalcitabine   1:4 (1:1) 0.61 (0.48, 0.73) 0.56 (0.39, 0.73)0.53 (0.28, 0.79)  1:10 (1:2.5) 0.55 (0.44, 0.66) 0.40 (0.31, 0.49) 0.30(0.18, 0.42)   5:8 (2.5:1) 0.80 (0.62, 0.97) 0.82 (0.58, 1.07) 0.86(0.46, 1.26) Emtricitabine   1:8 (1:1) 0.31 (0.27, 0.36) 0.23 (0.18,0.28) 0.18 (0.12, 0.24)  1:20 (1:2.5) 0.31 (0.26, 0.37) 0.23 (0.19,0.29) 0.17 (0.12, 0.28)  5:16 (2.5:1) 0.33 (0.28, 0.38) 0.25 (0.20,0.30) 0.19 (0.13, 0.25) ^(a)Ratio of Example 19 to comparator compound^(b)A lower bound of the asymptotic confidence interval greater than 1indicates antagonisms, an upper bound of less than 1 indicates synergismand a value of 1 being contained in the interval indicates additivity.The 95% confidence intervals are shown in parenthesis, and represent ameasure of variability in the data.

Two-Drug Combinations of Example 19 with Non-Nucleoside ReverseTranscriptase Inhibitors. Three non-nucleoside RT inhibitors werecombined with Example 19 at a range of concentrations near the EC₅₀value of each compound, as described above for nucleoside RT inhibitors.Data is presented in Table 5 as the combination indices and theasymptotic confidence intervals at different molar ratios. Of the three,nevaripine shows strong synergistic effects in combination with Example19. Synergy is seen at all effective concentrations and at all molarratios. Sustiva and nevirapine also exhibit combination indicesindicative of synergism at most effective concentrations and molarratios. However, in some cases, the upper range of the asymptoticconfidence interval is greater than 1, so an additive effect can not beruled out. No enhanced cytotoxicity was observed at the highestconcentrations tested with any of the drug combinations, suggesting apotential for therapeutic efficacy of Example 19 combinations withnon-nucleoside RT inhibitors.

TABLE 5 Two-Drug Combinations using Example 19 and Non-NucleosideReverse Transcriptase Inhibitors. Combination Indices at % HIVInhibition^(b) Molar Ratio (Confidence Interval) (EC₅₀ Ratio)^(a) 50%75% 90% Efavirenz  5:2 (1:1) 0.83 (0.75, 0.92) 0.76 (0.64, 0.88) 0.70(0.54, 0.85)  1:1 (1:2.5) 0.95 (0.86, 1.04) 0.93 (0.85, 1.02) 0.93(0.79, 1.06) 25:4 (2.5:1) 1.01 (0.92, 1.10) 0.96 (0.83, 1.10) 0.94(0.73, 1.14) Nevirapine  1:2 (1:1) 0.72 (0.62, 0.82) 0.69 (0.55, 0.83)0.66 (0.46, 0.87)  1:5 (1:2.5) 0.76 (0.64, 0.87) 0.81 (0.64, 0.97) 0.87(0.59, 1.15)  5:4 (2.5:1) 0.73 (0.62, 0.83) 0.68 (0.55, 0.81) 0.64(0.45, 0.84) Delavirdine  1:2 (1:1) 0.76 (0.64, 0.89) 0.60 (0.47, 0.74)0.48 (0.31, 0.64)  1:5 (1:2.5) 0.68 (0.58, 0.77) 0.44 (0.32, 0.54) 0.28(0.17, 0.39)  5:4 (2.5:1) 0.80 (0.68, 0.92) 0.53 (0.42, 0.63) 0.35(0.25, 0.45) ^(a)Ratio of Example 19 to comparator compound. ^(b)A lowerbound of the asymptotic confidence interval greater than 1 indicatesantagonisms, an upper bound of less than 1 indicates synergism, and avalue of 1 being contained in the interval indicates additivity. The 95%confidence intervals are shown in parenthesis, and represent a measureof variability in the data.

Two-Drug Combinations Involving Example 19 and HIV Protease Inhibitors.Evaluation of Example 19 for drug combination therapy with proteaseinhibitors was carried out using indinavir, amprenavir, nelfinavir,lopinavir, saquinavir, ritonavir and atazanavir. Results from thistwo-drug combination study are summarized in Table 6. Again, thecombination indices observed with Example 19 and all protease inhibitorsat almost all effective levels and molar ratios are suggestive of asynergistic relationship. This is especially true for saquinavir andatazanavir, where the confidence interval is below one at allconcentrations and effective levels. Meanwhile, the upper range of theconfidence interval is greater than one in only one condition forritonavir, indinavir and lopinavir, so an additive relationship withExample 19 cannot be ruled out. In addition, the upper range of theconfidence interval for nelfinavir and amprenavir are slightly greaterthan 1 under a few conditions, suggestive of a synergistic-additiveeffect for these compounds with Example 19. No cytotoxicity was observedat the highest concentrations used in any of these combination antiviralassays.

TABLE 6 Two-Drug Combination using Example 19 and Protease Inhibitors.Combination Indices at % HIV Inhibition^(b) Molar Ratio (ConfidenceInterval) (EC₅₀ Ratio)^(a) 50% 75% 90% Indinavir  1:1 (1:1) 0.86 (0.80,0.92) 0.71 (0.62, 0.81) 0.60 (0.46, 0.73)  2:5 (1:2.5) 0.92 (0.84, 0.99)0.84 (0.76, 0.92) 0.77 (0.66, 0.89)  5:2 (2.5:1) 0.94 (0.87, 1.02) 0.79(0.71, 0.87) 0.67 (0.57, 0.77 Nelfinavir  1:1 (1:1) 0.79 (0.73, 0.86)0.75 (0.67, 0.82) 0.71 (0.56, 0.84)  2:5 (1:2.5) 0.97 (0.89, 1.06) 0.87(0.79, 0.95) 0.78 (0.68, 0.88)  5:2 (2.5:1) 1.09 (1.00, 1.18) 0.98(0.89, 1.08) 0.90 (0.76, 1.03) Saquinavir  1:1 (1:1) 0.77 (0.70, 0.84)0.67 (0.58, 0.75) 0.58 (0.47, 0.69)  2:5 (1:2.5) 0.43 (0.38, 0.48) 0.51(0.42, 0.59) 0.59 (0.44, 0.74)  5:2 (2.5:1) 0.81 (0.72, 0.89) 0.77(0.66, 0.89) 0.74 (0.57, 0.91) Amprenavir  1:1 (1:1) 0.83 (0.67, 1.00)0.84 (0.61, 1.08) 0.89 (0.50, 1.23)  2:5 (1:2.5) 0.84 (0.69, 0.99) 0.77(0.58, 0.96) 0.75 (0.46, 1.04)  5:2 (2.5:1) 0.90 (0.77, 1.04) 0.62(0.50, 0.74) 0.44 (0.30, 0.57) Atazanavir  5:2 (1:1) 0.87 (0.79, 0.96)0.67 (0.55, 0.80) 0.52 (0.37, 0.67)  1:1 (1:2.5) 0.65 (0.51, 0.78) 0.45(0.31, 0.58) 0.31 (0.19, 0.44) 25:4 (2.5:1) 0.78 (0.69, 0.86) 0.60(0.54, 0.67) 0.47 (0.40, 0.54) Lopinavir  1:1 (1:1) 0.74 (0.67, 0.82)0.77 (0.66, 0.88) 0.84 (0.65, 1.02)  2:5 (1:2.5) 0.77 (0.66, 0.88) 0.56(0.36, 0.75) 0.41 (0.19, 0.64)  5:2 (2.5:1) 0.76 (0.69, 0.83) 0.62(0.55, 0.70) 0.54 (0.47, 0.61) Ritonavir  1:1 (1:1) 0.80 (0.67, 0.93)0.57 (0.41, 0.73) 0.44 (0.23, 0.65)  2:5 (1:2.5) 0.73 (0.59, 0.88) 0.64(0.48, 0.80) 0.61 (0.38, 0.85)  5:2 (2.5:1) 0.92 (0.72, 1.11) 0.72(0.50, 0.93) 0.59 (0.32, 0.87) ^(a)Ratio of Example 19 to comparatorcompound. ^(b)A lower bound of the asymptotic confidence intervalgreater than 1 indicates antagonisms, an upper bound of less than 1indicates synergism, and a value of 1 being contained in the intervalindicates additivity. The 95% confidence intervals are shown inparenthesis, and represent a measure of variability in the data.

Two-Drug Combination of Example 19 with Enfuvirtide. Enfuvirtide (T-20)is an HIV gp41 fusion inhibitor and the first approved entry classinhibitor. The results presented in Table 7 indicate that thecombination of Example 19 with T-20 is synergistic. No significantcytotoxicity was observed at the highest concentration of the combineddrugs.

TABLE 7 Two-Drug Combination study of Example 19 with Enfuvirtide.Combination Indices at % HIV Inhibition^(b) Molar Ratio (ConfidenceInterval) (EC₅₀ Ratio)^(a) 50% 75% 90% Enfuvirtide  5:44 (1:1) 0.68(0.59, 0.77) 0.59 (0.48, 0.70) 0.52 (0.37, 0.67)  1:22 (1:2.5) 0.75(0.65, 0.85) 0.60 (0.49, 0.70) 0.48 (0.34, 0.61) 25:88 (2.5:1) 0.76(0.65, 0.86) 0.73 (0.59, 0.86) 0.71 (0.50, 0.92) ^(a)Ratio of Example 19to comparator compound. ^(b)A lower bound of the asymptotic confidenceinterval greater than 1 indicates antagonisms, an upper bound of lessthan 1 indicates synergism, and a value of 1 being contained in theinterval indicates additivity. The 95% confidence intervals are shown inparenthesis, and represent a measure of variability in the data.

Pharmaceutical Composition and Methods of Use

The compounds of this invention inhibit HIV integrase. HIV integraseinhibitors belonging to a class of diketo acid compounds prevented viralintegration and inhibited HIV-1 replication in cells (Hazuda et al.Science 2000, 287, 646). Recently, HIV integrase inhibitors have beenaccepted into clinical trials for treating AIDS and HIV infection(Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke DrugsFut. 2002, 27, 1101).

Accordingly, another aspect of the invention is a method for treatingHIV infection in a human patient comprising administering atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, with apharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating HIV infectionin a human patient comprising the administration of a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, with a therapeutically effectiveamount of at least one other agent used for treatment of AIDS or HIVinfection selected from the group consisting of nucleoside HIV reversetranscriptase inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIVattachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding ormaturation inhibitors, and HIV integrase inhibitors.

Another aspect of the invention is a method wherein the agent is anucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the nucleoside HIVreverse transcriptase inhibitor is selected from the group consisting ofabacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir,zalcitabine, and zidovudine, or a pharmaceutically acceptable salt orsolvate thereof.

Another aspect of the invention is a method wherein the agent is anon-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the non-nucleosideHIV reverse transcriptase inhibitor is selected from the groupconsisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVprotease inhibitor.

Another aspect of the invention is a method wherein the HIV proteaseinhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVfusion inhibitor.

Another aspect of the invention is a method wherein the HIV fusioninhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptablesalt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVattachment inhibitor.

Another aspect of the invention is a method wherein the agent is a CCR5inhibitor.

Another aspect of the invention is a method wherein the CCR5 inhibitoris selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140,and UK-427,857, or a pharmaceutically acceptable salt or solvatethereof.

Another aspect of the invention is a method wherein the agent is a CXCR4inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitoris AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVbudding or maturation inhibitor.

Another aspect of the invention is a method wherein the budding ormaturation inhibitor is PA-457, or a pharmaceutically acceptable salt,or solvate thereof.

Another aspect of the invention is a method wherein the agent is an HIVintegrase inhibitor.

Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt or solvate thereof, with atleast one other agent used for treatment of AIDS or HIV infectionselected from the group consisting of nucleoside HIV reversetranscriptase inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIVattachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding ormaturation inhibitors, and HIV integrase inhibitors, and apharmaceutically acceptable carrier.

Another aspect of the invention is the composition wherein the agent isa nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is the composition wherein thenucleoside HIV transcriptase inhibitor is selected from the groupconsisting of abacavir, didanosine, emtricitabine, lamivudine,stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceuticallyacceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isa non-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is the composition wherein thenon-nucleoside HIV reverse transcriptase inhibitor is selected from thegroup consisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV protease inhibitor.

Another aspect of the invention is the composition wherein the HIVprotease inhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV fusion inhibitor.

Another aspect of the invention is the composition method wherein theHIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceuticallyacceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV attachment inhibitor.

Another aspect of the invention is the composition wherein the agent isa CCR5 inhibitor.

Another aspect of the invention is the composition wherein the CCR5inhibitor is selected from the group consisting of Sch-C, Sch-D,TAK-220, PRO-140, and UK-427,857, or a pharmaceutically acceptable saltor solvate thereof.

Another aspect of the invention is a method wherein the agent is a CXCR4inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitoris AMD-3100 or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV budding or maturation inhibitor.

Another aspect of the invention is the composition wherein the buddingor maturation inhibitor is PA-457, or a pharmaceutically acceptable saltor solvate thereof.

Another aspect of the invention is the composition wherein the agent isan HIV integrase inhibitor.

“Combination,” “coadministration,” “concurrent,” and similar termsreferring to the administration of a compound of Formula I with at leastone anti-HIV agent mean that the components are part of a combinationantiretroviral therapy or highly active antiretroviral therapy (HAART)as understood by practitioners in the field of AIDS and HIV infection.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of AIDS and HIV infection. In general, the goals of treatmentare suppression of viral load, restoration and preservation ofimmunologic function, improved quality of life, and reduction ofHIV-related morbidity and mortality.

“Patient” means a person infected with the HIV virus and suitable fortherapy as understood by practitioners in the field of AIDS and HIVinfection.

“Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” andrelated terms are used as understood by practitioners in the field ofAIDS and HIV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of Formula I or its pharmaceutically acceptable salt and apharmaceutically acceptable carrier and may contain conventionalexcipients. A therapeutically effective amount is that which is neededto provide a meaningful patient benefit. Pharmaceutically acceptablecarriers are those conventionally known carriers having acceptablesafety profiles. Compositions encompass all common solid and liquidforms including capsules, tablets, losenges, and powders as well asliquid suspensions, syrups, elixers, and solutions. Compositions aremade using common formulation techniques, and conventional excipients(such as binding and wetting agents) and vehicles (such as water andalcohols) are generally used for compositions.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agentswill be present in a unit range similar to agents of that class usedclinically. Typically, this is 0.25–1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1–100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other antiretroviral agents will be present in a unitrange similar to agents of that class used clinically. Typically, thisis 1–100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other antiretroviral agents used clinically. Typically,the daily dose will be 1–100 mg/kg body weight daily. Generally, morecompound is required orally and less parenterally. The specific dosingregime, however, will be determined by a physician using sound medicaljudgement.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating AIDS and HIVinfection. Some of these agents include HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integraseinhibitors, HIV nucleoside reverse transcriptase inhibitors, HIVnon-nucleoside reverse transcriptase inhibitors, HIV proteaseinhibitors, budding and maturation inhibitors, immunomodulators, andanti-infectives. In these combination methods, the compound of Formula Iwill generally be given in a daily dose of 1–100 mg/kg body weight dailyin conjunction with other agents. The other agents generally will begiven in the amounts used therapeutically. The specific dosing regime,however, will be determined by a physician using sound medicaljudgement.

Table 8 lists some agents useful in treating AIDS and HIV infectionwhich are suitable for this invention.

TABLE 8 DRUG NAME MANUFACTURER INDICATION ANTIVIRALS 097 Hoechst/BayerHIV infection, AIDS, (non-nucleoside ARC reverse transcriptaseinhibitor) Amprenavir Glaxo Wellcome HIV infection, AIDS, 141 W94 ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, AIDS, GW 1592 ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC,in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection, ARC, AL-721 Ethigen PGL HIV positive,AIDS (Los Angeles, CA) Alpha Interferon Glaxo Wellcome Kaposi's sarcomaHIV in combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha (Rockville, MD) aberrantInterferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-MyersSquibb/ HIV infection, AIDS, (CGP-73547) Novartis ARC (proteaseinhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, AIDS,(CGP-61755) Novartis ARC (protease inhibitor) CI-1012 Warner-LambertHIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes,papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral, CMV retinitis DelaviridinePharmacia-Upjohn HIV infection, AIDS, (RT inhibitor) ARC Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomaticJapan) ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, AIDS, (proteaseinhibitor) (Camden, NJ) ARC Efavirenz DuPont Merck HIV infection, AIDS,(DMP 266) ARC (−)6-Chloro-4-(S)- cyclopropylethynyl- 4(S)-trifluoro-methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE (non-nucleosideRT inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA)Famciclovir Smith Kline herpes zoster, herpes simplex FTC EmoryUniversity HIV infection, AIDS, (reverse ARC transcriptase inhibitor) GS840 Gilead HIV infection, AIDS, (reverse ARC transcriptase inhibitor)HBY097 Hoechst Marion HIV infection, AIDS, (non-nucleoside Roussel ARCreverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection,AIDS, ARC Recombinant Triton Biosciences AIDS, Kaposi's sarcoma, Human(Almeda, CA) ARC Interferon Beta Interferon alfa-n3 Interferon SciencesARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer InstituteHIV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection,AIDS, (reverse ARC, also with AZT transcriptase inhibitor) LobucavirBristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,AIDS, (protease inhibitor) Pharmaceuticals ARC Nevirapine BoeheringerHIV infection, AIDS, (RT inhibitor) Ingleheim ARC Novapren NovaferonLabs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDSOctapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis,HIV Phosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, (protease inhibitor)ARC Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, AIDS, Tech (Houston, TX) ARC Ritonavir Abbott HIV infection,AIDS, (protease inhibitor) ARC Saquinavir Hoffmann- HIV infection, AIDS,(protease inhibitor) LaRoche ARC Stavudine; d4T Bristol-Myers Squibb HIVinfection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir GlaxoWellcome Genital HSV & CMVinfections Virazole Viratek/ICN asymptomaticHIV- Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIVinfection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC,Kaposi's sarcoma, in combination with other therapies Tenofovir GileadHIV infection, AIDS disoproxil, fumarate salt (Viread ®) (reversetranscriptase inhibitor) Combivir ® GSK HIV infection, AIDS (reversetranscriptase inhibitor) abacavir succinate GSK HIV infection, AIDS (orZiagen ®) (reverse transcriptase inhibitor) Reyataz ® Bristol-MyersSquibb HIV infection, AIDS (atazanavir) Fuzeon Roche/Trimeris HIVinfection, AIDS, (Enfuvirtide, T-20) viral fusion inhibitor Trizivir ®HIV infection, AIDS Kaletra ® Abbott HIV infection, AIDS, ARCIMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia UpjohnAdvanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)CL246,738 American Cyanamid AIDS, Kaposi's sarcoma Lederle Labs EL10Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharmBlocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, incombination w/TNF (tumor necrosis factor) Granulocyte Genetics InstituteAIDS Macrophage Colony Sandoz Stimulating Factor GranulocyteHoechst-Roussel AIDS Macrophage Colony Immunex Stimulating FactorGranulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZTStimulating Factor HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's sarcoma, (New Orleans, LA) ARC, PGL IMREG-2 Imreg AIDS,Kaposi's sarcoma, (New Orleans, LA) ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma AIDS,Muramyl-Tripeptide Amgen in combination w/AZT Granulocyte ColonyStimulating Factor Remune Immune Response Immunotherapeutic Corp. rCD4Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARChybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma, AIDS, Alfa 2a in combination w/AZTARC SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of oral Nystatin Pastille candidiasis Ornidyl MerrellDow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate(Rosemont, IL) (IM & IV) Trimethoprim Antibacterial Trimethoprim/sulfaAntibacterial Piritrexim Burroughs Wellcome PCP treatment PentamidineFisons Corporation PCP prophylaxis Isethionate for Inhalation SpiramycinRhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm.Histoplasmosis; R51211 cryptococcal meningitis TrimetrexateWarner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcomaRecombinant Ortho Pharm. Corp. Severe anemia assoc. Human with AZTtherapy Erythropoietin Recombinant Serono AIDS-related wasting, Humancachexia Growth Hormone Megestrol Acetate Bristol-Myers Squibb Treatmentof anorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and NutritionPharmaceuticals malabsorption related to AIDS

DESCRIPTION OF SPECIFIC EMBODIMENTS

2-(2-(Methylthio)ethoxy)acetic acid. A solution of 2-methylthioethanol(10.0 g, 0.108 mol) in dry tetrahydrofuran (25 ml) was added dropwise,over 30 min, to a suspension of sodium hydride (9.54 g of a 60%dispersion in mineral oil, 0.238 mol, washed twice with hexane) in drytetrahydrofuran (250 ml) at 22° C. After 30 min, a solution ofchloroacetic acid (10.25 g, 0.108 mol) in dry tetrahydrofuran (20 ml)was added dropwise, over 30 min at 22° C., and the resulting mixture wasthen heated under reflux for 5 h. The cooled mixture was treated with250 ml of 1 N hydrochloric acid and sodium chloride added to the aqueousphase until saturation. The organic phase was separated and the aqueousphase washed with ethyl acetate. The combined organic extracts werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Distillation of the resultingresidue in vacuo gave 11.27 g (69% yield) of the title acid as a clearoil; bp 85–95° C./0.3 torr (bulb to bulb distillation, air bathtemperature). ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.18 (3H, s, SCH₃), 2.76 (2H,t, J=6.6 Hz, CH₂), 3.77 (2H, t, J=6.6 Hz, CH₂), 4.20 (2H, s, OCH₂).

Methyl 2-(2-(methylthio)ethoxy)acetate. A solution of intermediate1,2-(2-(methylthio)ethoxy)acetic, (11.27 g, 0.075 mol) in drydichloromethane (50 ml) was treated with oxalylchloride (13.0 ml, 0.15mol) followed by a drop of N,N-dimethylformamide and the resultingmixture stirred at 22° C. for 5 h. The solvent and excess reagent werethen evaporated under reduced pressure and the residual acid chloridewas added dropwise to a cold mixture (0–5° C.) of methanol (30 ml) andpyridine (10 ml) in dichloromethane (50 ml). After 1 h at 22° C., thesolvent was evaporated under reduced pressure. The resulting residue wasdiluted with ethyl acetate, washed with 1 N hydrochloric acid, saturatedsodium bicarbonate and brine, dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. Distillation of the resultingresidue in vacuo gave 11.42 g (93% yield) of the title ester as a clearoil; bp 65–75° C./0.1 torr (bulb to bulb distillation, air bathtemperature). ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.17 (3H, s, SCH₃), 2.75 (2H,t, J=6.9 Hz, CH₂), 3.74 (2H, t, J=6.9 Hz, CH₂), 3.77 (3H, s, OCH₃), 4.15(2H, s, OCH₂).

2-(2-(Methylthio)ethoxy)acetamidine hydrochloride salt. Intermediate 2,methyl 2-(2-(methylthio)ethoxy)acetate, (4.69 g, 28.6 mmol) was added toa solution of methylchloroaluminum amide (H. Geilen, C. Alonso-Alija, M.Hendrix, U. Niewohner and D. Schauss, Tetrahedron Lett., 2002, 43,419–421)(0.114 mol; prepared in toluene (50 ml) from ammonium chloride6.30 g (0.117 mol) and 57.0 ml (0.114 mol) of a 2 M solution oftrimethylaluminum in toluene) and the resulting mixture was heated at80° C. for 18 h. The reaction mixture was then cooled to 0° C., treateddropwise with methanol (100 ml) and stirred for another hour at 25° C.The solid which was formed was filtered and washed with methanol (300ml). The combined filtrate was concentrated to give a white paste whichwas diluted with isopropanol (160 ml) and acetone (40 ml) and stirred at25° C. for 1 h. The solid was then filtered off and the filtrateconcentrated in vacuo to give 3.50 g (62% yield) of the title compoundas an oil. ¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.10 (3H, s, SCH₃), 2.71 (2H,t, J=6.8 Hz, CH₂), 3.66 (2H, t, J=6.8 Hz, CH₂), 4.34 (2H, s, OCH₂). MS(ESI+) m/z 149 [M+H⁺].

Ethyl5-benzyloxy-2-{(2-(methylthio)ethoxy)methyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylate.Diethyl oxalate (2.77 g, 19.0 mmol) and ethyl benzyloxyacetate (3.69 g,19.0 mmol) in dry tetrahydrofuran (30 ml) were treated at 22° C. withsodium hydride (0.83 g of a 60% dispersion in mineral oil, 20.9 mmol)followed by ethanol (10 μl) and the resulting mixture was stirred at 22°C. for 18 h. The tetrahydrofuran was evaporated under reduced pressureto give an orange syrup. A mixture of intermediate3,2-(2-(methylthio)ethoxy)acetamidine hydrochloride salt, (3.50 g, 19.0mmol) in a solution of sodium ethoxide (9.5 mmol, prepared from 0.22 gof sodium in ethanol 25 ml) was then added all at once to the aboveadduct and the resulting mixture heated at 60° C. for 3 h. Acetic acid(2 ml) was added and the ethanol was evaporated under reduced pressure.The residue was diluted with ethyl acetate washed successively withsaturated sodium bicarbonate and brine, then dried over anhydrousmagnesium sulfate and concentrated under reduced pressure.Chromatography on silica gel (elution with a gradient of ethyl acetate20–30% in toluene) gave 0.728 g (10% yield) of the title ester as aclear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH₃),2.18 (3H, s, SCH₃), 2.78 (2H, t J=6.0 Hz, CH₂), 3.78 (2H, t, J=6.0 Hz,CH₂), 4.36 (2H, q, J=7.1 Hz, OCH₂), 4.54 (2H, s, OCH₂), 5.35 (2H, s,OCH₂), 7.37 (3H, m, aromatics), 7.48 (2H, m, aromatics). HRMS (ESI⁺)calculated for C₁₈H₂₃N₂O₅S [M+H⁺]: 379.1328: found: 379.1314.

Ethyl5-benzyloxy-2-{(2-(dimethylsulfonium)ethoxy)methyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylateiodide. A solution of intermediate 4, ethyl5-benzyloxy-2-{(2-(methylthio)ethoxy)methyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(0.555 g, 1.47 mmol) in dichloromethane (10 ml) was treated at 22° C.with iodomethane (2.0 ml, 21.5 mmol) for 10 days. Evaporation of thesolvent and excess reagent gave the title compound (0.76 g) as an oilwhich was used without further purification. ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.32 (3H, t, J=7.1 Hz, CH₃), 3.26 (6H, s, SCH₃), 4.02 (2H, m,CH₂), 4.23 (2H, m, CH₂), 4.34 (2H, q, J=7.1 Hz, OCH₂), 4.69 (2H, s,OCH₂), 5.23 (2H, s, OCH₂), 7.35–7.5 (5H, m, aromatics). MS (ESI⁺) m/z393 [M⁺].

Ethyl3-benzyloxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of intermediate 5, ethyl5-benzyloxy-2-{(2-(dimethylsulfonium)ethoxy)methyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylateiodide, (0.76 g, 1.47 mmol) in dry N,N-dimethylformamide (10 ml) wastreated at 22° C. with powdered anhydrous potassium carbonate (2.5 g)and the resulting mixture stirred for 48 h. The solid was then filteredand the filtrate evaporated in vacuo. The residue was diluted with ethylacetate washed successively with 0.1 N hydrochloric acid, saturatedsodium bicarbonate, brine and dried over anhydrous magnesium sulfate.Evaporation of the solvent followed by chromatography on silica gel(elution with a gradient of ethyl acetate 20–50% in toluene) gave 0.347g (72% yield) of the title ester as white prisms; mp 103–104° C. (ethylacetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.34 (3H, t, J=7.1 Hz,CH₃), 4.03 (2H, t, J=5.6 Hz, CH₂), 4.11 (2H, t, J=5.6 Hz, CH₂), 4.37(2H, q, J=7.1 Hz, OCH₂), 4.74 (2H, s, OCH₂), 5.30 (2H, s, OCH₂), 7.38(3H, m, aromatics), 7.50 (2H, m, aromatics). Anal. Calcd for C₁₇H₁₈N₂O₅:C, 61.81; H, 5.49; N, 8.48. Found: C, 61.55; H, 5.53; N, 8.39.

3-(Benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid.

A solution of intermediate 6, ethyl3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(0.300 g, 0.91 mmol) in ethanol (10 ml) was treated with 3 ml (3.0 mmol)of 1 N sodium hydroxide and stirred at 25° C. for 30 min. The solutionwas then acidified with 1 N hydrochloric acid, extracted with ethylacetate, washed with brine and dried over anhydrous magnesium sulfate.Evaporation of the solvent gave 0.264 g (96% yield) of the title acid aswhite crystals; mp 171° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 4.03 (2H, t, J=5.3 Hz, CH₂), 4.12 (2H, t, J=5.3 Hz, CH₂), 4.73(2H, s, OCH₂), 5.53 (2H, s, OCH₂), 7.35–7.42 (3H, m, aromatics), 7.53(2H, m, aromatics). Anal. Calcd for C₁₅H₁₄N₂O₅: C, 59.60; H, 4.67; N,9.27. Found: C, 59.35; H, 4.69; N, 9.10.

Ethyl3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.

A solution of intermediate 6, ethyl3-benzyloxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.236 g, 0.714 mmol) in a mixture of ethyl acetate (60 ml) and ethanol(20 ml) was treated with 1 atm of hydrogen at 25° C. over 10% palladiumon activated carbon (0.10 g) for 2.5 h to give 0.160 g (94% yield) ofthe title compound as white needles; mp 172–174° C. (ethyl acetate).¹HNMR 400 MHz (CDCl₃) δ ppm: 1.47 (3H, t, J=7.3 Hz, CH₃), 4.08 (4H, m,2×CH₂), 4.54 (2H, q, J=7.3 Hz, OCH₂), 4.72 (2H, s, OCH₂), 10.75 (1H, s,OH). Anal. Calcd for C₁₀H₁₂N₂O₅: C, 50.00; H, 5.03; N, 11.66. Found: C,50.01; H, 4.95; N, 11.54.

2-(2-(Methylthio)ethoxy)propanoic acid.

Addition of 2-methylthioethanol (10.0 g, 0.108 mol) to sodium hydride(9.54 g of a 60% dispersion in mineral oil, 0.238 mol, washed twice withhexane) followed by reaction with 2-bromopropionic acid (16.6 g, 0.108mol) gave 13.81 g (78% yield) of the title compound as a clear oil; bp80–90° C./0.2 torr (bulb to bulb distillation, air bath temperature).¹HNMR 400 MHz (CDCl₃) δ ppm: 1.49 (3H, d, J=7.0 Hz, CH₃), 2.18 (3H, s,SCH₃), 2.76 (2H, t, J=6.6 Hz, CH₂), 3.74 (2H, t, J=6.6 Hz, CH₂), 4.07(1H, d, J=7.0 Hz, OCH).

Methyl 2-(2-(methylthio)ethoxy)propanoate.

Reaction of intermediate 9,2-(2-(methylthio)ethoxy)propanoic acid,(13.70 g, 0.083 mol) with oxalyl chloride followed by reaction withmethanol gave 14.27 g (96% yield) of the title ester as a clear oil; bp55–60° C./0.3 torr (bulb to bulb distillation, air bath temperature).¹HNMR 400 MHz (CDCl₃) δ ppm: 1.42 (3H, d, J=7.0 Hz, CH₃), 2.15 (3H, s,SCH₃), 2.71 (2H, t, J=6.8 Hz, CH₂), 3.56 (1H, m, CH), 3.75 (3H, s,OCH₃), 3.78 (1H, m, CH), 4.15 (1H, q, J=7.0 Hz, OCH).

2-(2-(Methylthio)ethoxy)propanamidine hydrochloride salt.

Intermediate 10, methyl 2-(2-(methylthio)ethoxy)propanoate, (10.00 g,56.1 mmol) was added to a solution of methylchloroaluminum amide (0.224mol; prepared in toluene (100 ml) from ammonium chloride 12.36 g (0.231mol) and 112.0 ml (0.224 mol) of a 2 M solution of trimethylaluminum intoluene} as described in the preparation of intermediate 3 to give 7.70g (69% yield) of the title compound as an oil. ¹HNMR 400 MHz (D₂O) δppm: 1.37 (3H, d, J=6.6 Hz, CH₃), 2.01 (3H, s, SCH₃), 2.65 (2H, t, J=5.6Hz, CH₂), 3.64 (2H, m, CH₂), 4.30 (1H, q, J=6.6 Hz, OCH). MS (ESI⁺) m/z163 [M+H⁺].

Ethyl5-benzyloxy-2-{1-(2-(methylthio)ethoxy)ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylate.

Diethyl oxalate (5.66 g, 38.7 mmol) and ethyl benzyloxyacetate (7.52 g,38.7 mmol) in dry tetrahydrofuran (60 ml) were treated at 22° C. withsodium hydride (1.70 g of a 60% dispersion in mineral oil, 42.5 mmol)and the condensation product was reacted with a mixture of intermediate11, 2-(2-(methylthio)ethoxy)propanamidine hydrochloride salt, (7.70 g,38.7 mmol) in a solution of sodium ethoxide (19.3 mmol, prepared from0.445 g of sodium) in ethanol (50 ml) to give 2.29 g (15% yield) of thetitle ester as a clear oil after chromatography on silica gel. ¹HNMR 400MHz (CDCl₃) δ ppm: 1.33 (3H, t, J=7.1 Hz, CH₃), 1.54 (3H, d, J=7.1 Hz,CH₃), 2.16 (3H, s, SCH₃), 2.7–2.8 (2H, m, CH₂), 3.54 (1H, m, CH), 3.86(1H, m, CH), 4.37 (2H, q, J=7.1 Hz, OCH₂), 4.47 (1H, q, J=7.1 Hz, OCH),5.34 (2H, ABq, J_(AB)=11.0 Hz, OCH₂), 7.37 (3H, m, aromatics), 7.49 (2H,m, aromatics). MS (ESI+) m/z 393 [M+H⁺].

Ethyl5-benzyloxy-2-{1-(2-(dimethylsulfonium)ethoxy)ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylateiodide.

A solution of intermediate 12, ethyl5-benzyloxy-2-{1-(2-(methylthio)ethoxy)ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(1.63 g, 4.15 mmol) in dichloromethane (5 ml) was treated at 22° C. withiodomethane (5.0 ml, 53.9 mmol) for 5 days as described for thepreparation of intermediate 5, to give the title compound (2.22 g) as anoil which was used without further purification. ¹HNMR 400 MHz (CDCl₃) δppm: 1.32 (3H, t, J=7.1 Hz, CH₃), 1.66 (3H, d, J=6.6 Hz, CH₃), 3.15 (3H,s, SCH₃), 3.32 (3H, s, SCH₃), 3.4 (1H, m, CH), 4.01 (2H, m, CH₂), 4.37(2H, q, J=7.1 Hz, OCH₂), 4.45 (1H, m, CH), 4.63 (1H, q, J=6.6 Hz, OCH),5.28 (2H, OCH₂), 7.38 (3H, m, aromatics), 7.50 (2H, m, aromatics). MS(ESI⁺) m/z 407 [M+].

Ethyl3-(benzyloxy)-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.

A solution of intermediate 13, ethyl5-benzyloxy-2-{1-(2-(dimethylsulfonium)ethoxy)ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxylateiodide (2.22 g, 4.15 mmol) in dry N,N-dimethylformamide (30 ml) wastreated at 22° C. with powdered anhydrous potassium carbonate (6 g) andstirred for 40 h. The solid was then filtered and the filtrate wasconcentrated in vacuo. The residue was diluted with ethyl acetate,washed with 0.1 N hydrochloric acid, saturated sodium bicarbonate andbrine then dried over anhydrous magnesium sulfate. Evaporation of thesolvent and chromatography of the residue on silica gel (elutiontoluene-ethyl acetate 7:3) gave 1.0 g (70% yield) of the title ester aswhite crystals; mp 48–50° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) 6 (Ppm): 1.33 (3H, t, J=7.1 Hz, CH₃), 1.68 (3H, d, J=6.6 Hz,CH₃), 3.91 (2H, m, CH₂), 4.17–4.31 (2H, m, CH₂), 4.37 (2H, q, J=7.1 Hz,OCH₂), 4.73 (1H, q, J=6.6 Hz, OCH), 5.30 (2H, ABq, J_(AB)=11.0 Hz,OCH₂), 7.38 (3H, m, aromatics), 7.50 (2H, m, aromatics). Anal. Calcd forC₁₈H₂₀N₂O₅: C, 62.78; H, 5.85; N, 8.13. Found: C, 62.69; H, 6.01; N,8.16.

Ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.

Hydrogenolysis of intermediate 14, ethyl3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.610 g, 1.77 mmol) in a mixture of ethyl acetate (75 ml) and ethanol(75 ml) at 25° C. over 10% palladium on activated carbon (0.20 g) under1 atm of hydrogen for 2 h gave 0.430 g (95% yield) of the title ester aswhite crystals; mp 119–121° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.46 (3H, t, J=7.1 Hz, CH₃), 1.67 (3H, d, J=6.6 Hz, CH₃),3.90 (2H, m, CH₂), 4.13–4.32 (2H 4.51 (2H, m, OCH₂), 4.70 (1H, q, J=6.6Hz, CH), 10.7 (1H, broad, OH). Anal. Calcd for C₁₁H₁₄N₂O₅: C, 51.96; H,5.55; N, 11.01. Found: C, 51.60; H, 5.61; N, 10.70.

3-Benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid.

Saponification of intermediate 14, ethyl3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.225 g, 0.65 mmol) as described in the preparation of intermediate 7gave 0.198 g (96% yield) of the title acid as white crystals; mp167–168° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.68(3H, d, J=6.6 Hz, CH₃), 3.93 (2H, m, CH₂), 4.12–4.21 (1H, m, CH),4.27–4.35 (1H, m, CH), 4.70 (1H, q, J=6.6 Hz, OCH), 5.53 (2H, ABq,J_(AB)=11.1 Hz, OCH₂), 7.39 (3H, m, aromatics), 7.55 (2H, m, aromatics).MS (ESI⁺) m/z 317 [M+H⁺]. Anal. Calcd for C₁₆H₁₆N₂O₅: C, 60.75; H, 5.10;N, 8.86. Found: C 60.65; H, 5.05; N, 8.72.

2-(2-(Methylthio)ethyl)-1,3-dioxolane.

A solution of 3-(methylthio)propanal (5.2 g, 0.05 mol) andethyleneglycol (3.4 g. 0.055 mol) in 100 mL of benzene was treated with300 mg p-toluenesulfonic acid and heated at reflux for 4 hrs. Thesolution was cooled and decanted. Concentration and drying in vacuoprovided the title compound as a light yellow oil. ¹H NMR (300 MHz,CDCl₃) δ ppm: 4.93 (1H, t, J=4.76 Hz) 3.74–4.03 (4H, m) 2.46–2.68 (2H,m) 2.08 (3H, s) 1.83–2.00 (2H, m).

4-(Methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanenitrile.

Intermediate 17, 2-(2-(methylthio)ethyl)-1,3-dioxolane, (2.96 g, 0.02mol), trimethylsilylcyanide (1.98 g, 0.02 mol) and 20 mg zinc iodidewere combined under N₂ and stirred for 16 hrs at room temperature. Themixture was then concentrated in vacuo to provide 4.9 g (approximately100% yield) of the title compound as a yellow oil. ¹H NMR (300 MHz,CDCl₃) δ ppm: 4.37–4.49 (1H, m) 3.50–3.88 (4H, m) 2.57–2.74 (2H, m)1.98–2.26 (5H, m) 0.06–0.22 (9H, m): LC/MS 198 (−TMS+Na).

4-(Methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanamidine.

A solution of intermediate 18,4-(methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanenitrile, (4.9 g,0.02 mol) in 30 mL of methanol was saturated with ammonia. The flask wasthen sealed and heated in an oil bath at 80–90° C. for 16 hrs. Aftercooling, the flask was opened and the mixture concentrated in vacuo togive the title compound in essentially quantitative yield as a veryviscous oil. ¹H NMR (300 MHz, CDCl₃) δ ppm: 3.94–4.02 (1H, m) 3.76–3.94(3H, m) 3.68–3.77 (2H, m) 3.52–3.62 (2H, M) 2.53–2.67 (2H, m) 2.07 (3H,s) 1.89–2.01 (2H, m); LC/MS 193 (M+H).

Ethyl5-(benzyloxy)-2-(1-(2-hydroxyethoxy)-3-(methylthio)propyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate.

Ethyl 2-(benzyloxy)acetate (7.76 g, 0.04 mole) and diethyloxalate (5.84g, 0.04 mole) in 80 mL of tetrahydrofuran were treated with oneequivalent of NaH and a few drops of ethanol. The resulting mixture wasstirred for 1.5 hours after which the solvent was removed under vacuumand replaced with 30 mL of ethanol. Intermediate 19,2-(2-hydroxyethoxy)-4 methylthio)butanamidine, in 30 mL ethanol wasadded to the mixture followed by NaH (60% in mineral oil, 800 mg, 0.02mol). This was stirred for 20 hrs at room temperature and 3 hrs at 60°C. then concentrated under reduced pressure. The residue was dissolvedin CH₂Cl₂ and washed with water. The CH₂Cl₂ layer was dried over MgSO₄,filtered and concentrated under vacuum. Chromatography on silica gel,eluting with 4:1 CH₂Cl₂; ether and ethyl acetate, gave 760 mg of thetitle compound (9% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.24–7.54 (5H,m) 5.17–5.36 (2H, s) 4.50 (1H, m) 4.30 (2H, q, J=7.32 Hz) 3.38–4.00 (4H,m) 2.59 (2H, m) 1.95–2.11 (5H, m) 1.20–1.36 (3H, t, J=7.32 Hz); LC/MSm/z 423 (M+H).

Ethyl3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.

To a solution of intermediate 20, ethyl5-(benzyloxy)-2-(1-(2-hydroxyethoxy)-3-(methylthio)propyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(527 mg, 1.25 mmol) and Et₃N (505 mg, 5 mmol) dissolved in 10 mL ofCH₂Cl₂ was added a solution of CH₃SO₂Cl (288 mg, 2.5 mmol) dissolved in2 mL of CH₂Cl₂. This was stir-red for 20 hrs then concentrated. Thecrude product was purified by chromatography on silica gel, using 10:1CH₂Cl₂: ether as eluent, to give the title compound 265 mg (52% yield).(500 MHz, CDCl₃) δ ppm: 7.31–7.55 (5H, m) 5.30 (2H, s) 4.75 (1H, dd,J=3.66 Hz) 4.32–4.40 (2H, q, J=7.17 Hz) 4.13–4.30 (2H, m) 3.75–3.97 (2H,m) 2.20–2.84 (4H, m) 2.06 (3H, s) 1.32 (3H, t, J=7.17 Hz); LC/MS m/z 405(M+H).

3-(Benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid.

To a stirred solution of intermediate 21, ethyl3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(97 mg, 0.2 mmol) in 3 mL tetrahydrofuran was added lithium hydroxide(15 mg, 0.6 mmol) in 3 mL water. After 20 min the reaction mixture wasacidified with 1N HCl and extracted with CH₂Cl₂. The extract was driedover MgSO₄, filtered and concentrated to give 82 mg of the titlecompound (88% yield). LC/MS m/e 377.

2-(2-Chloroethoxy)-2-methylpropanenitrile.

(Navalokina, R. Et al J. Org. Chem. USSR (Engl. Trans.), 1980, 16,1382–1386.2) Ramalingam, K. U.S. Pat. No. 4,864,051, 1989.). A 250 mLround bottom flask was charged with ZnCl₂ (68.14 g, 0.5 mole) which wasthen fused by heating under vacuum. After returning to room temperaturethe material was placed under an atmosphere of N₂. To this was addedacetone cyanohydrin (45.66 mL, 0.5 mole) followed by 2-chloroethanol(50.24 mL, 0.75 mole) and the mixture placed in a preheated oil bath(60° C.). After stirring for 18–20 h at 60° C., the reaction mixture wascooled, diluted with water (300 mL) and washed with CH₂Cl₂ (5×100 mL).The combined CH₂Cl₂ extracts were dried (Na₂SO₄), filtered andconcentrated under vacuum to afford the crude product as a yellowliquid. Purification was accomplished by vacuum distillation (10 mm Hg)using a vigreux column. The fraction boiling between 65–75° C. wascollected to afford the desired product as a colorless oil (47.1 g,63.8% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm: 3.85 (2H, t, J=5.8 Hz),3.64 (2H, t, J=5.8 Hz), 1.60 (6H, s).

Ethyl2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate.

To a stirred solution of intermediate 23,2-(2-chloroethoxy)-2-methylpropanenitrile (14.7 g, 0.10 mole) and NaI(1.5 g, 10 mmol) in ethanol (50 mL) was added an aqueous solution (50%)of hydroxylamine (18.4 g, 0.30 mole) resulting in an exothermicreaction. Following this the reaction mixture was heated at 80° C. for 2h. Upon cooling to room temperature the solvent was removed. Theresulting residue was dissolved in 1:1 ethanol/H₂O (100 mL) and cooledin an ice bath. To this was added diethyl acetylenedicarboxylate (17.6mL, 0.110 mole) over 10 min. The reaction mixture was allowed to warm toroom temperature and stirred for 1 h. Following this, it was dilutedwith ethyl acetate (250 mL), washed with H₂O (2×100 mL), brine (50 mL),dried over Na₂SO₄, filtered and concentrated to give the crude productas a yellow oil. Flash chromatography on a silica gel column, elutingwith 20–40% ethyl acetate/Hexanes, provided the title compound as aviscous pale yellow oil (15.29 g, 48.6% yield). ¹H NMR (500 MHz, CDCl₃)δ ppm: 4.35–4.28 (2H, m), 4.18–4.12 (2H, m), 3.60–3.56 (1H, m),3.51–3.47 (1H, m), 3.30 (1H, d, J=16.2 Hz), 2.94 (1H, d, J=16.2 Hz),1.52 (3H, s), 1.51 (3H, s), 1.29 (3H, t, J=7.0 Hz), 1.24 (3H, t, J=7.0Hz). LCMS (M+H) calcd for C₁₄H₂₃N₂O₇: 315.16; found: 315.33.

Ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.

A solution of intermediate 24, ethyl2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate(31.16 g) in 1,2,4-trimethylbenzene (200 mL) was heated at 180° C. for 5h. The resulting dark reaction solution was cooled then concentrated togive a dark brown paste which was taken up into ethyl acetate (250 mL)and extracted with 0.5 M aq Na₂CO₃ (4×50 mL). The organic layer wasdiscarded and the aqueous layer acidified by carefully adding conc. HCl(20 mL) before being extracted with CH₂Cl₂ (4×50 mL). The combinedCH₂Cl₂ layers were dried (Na₂SO₄), filtered and concentrated to give adark paste which was dissolved in ether (100 mL) and allowed to stand atroom temperature in a open flask. The brown/light yellow solid thatformed was filtered to afford the title compound. The mother liquor thatcontained product was re-processed to afford additional material(combined yield ˜18–20% over two steps). ¹H NMR (500 MHz, CDCl₃) δ:10.55 (1H, s), 4.45 (2H, q, J=7.0 Hz), 4.02 (4H, s), 1.61 (6H, s), 1.43(3H, t, J=7.0 Hz). HRMS (M+H) calcd for C₁₂H₁₇N₂O₅: 269.1138; found:269.1149. Anal calcd for C₁₂H₁₆N₂O₅: C, 53.72; H, 6.01; N, 10.44. Found:C, 53.71; H, 6.04; N, 10.30.

Ethyl3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.

To a stirred solution of intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(2.68 g, 10 mmol) and benzyl bromide (1.43 mL, 12 mmol) in DMF (40 mL)was added K₂CO₃ (2.07 g, 20 mmol). After stirring 48 h at ambienttemperature, the reaction mixture was diluted with ether (100 mL), thenwashed with water (3×30 mL) and brine (20 mL). The organic layer wasdried (Na₂SO₄/activated carbon), filtered and concentrated to give ayellow solid. Trituration with hexanes/ether (9:1) afforded the titlecompound as an off-white solid (2.79 g, 78% yield). ¹H NMR (500 MHz,CDCl₃) δ ppm: 7.48–7.45 (2H, m), 7.37–7.30 (3H, m), 5.25 (2H, s), 4.33(2H, q, J=7.3 Hz), 4.05–3.99 (4H, m), 1.62 (6H, s), 1.29 (3H, t, J=7.3Hz). HRMS (M+H) calcd for C₁₉H₂₃N₂O₅: 359.1607; found: 359.1611. Analcalcd for C₁₉H₂₂N₂O₅: C, 63.67; H, 6.18; N, 7.81; found: C, 63.63; H,6.16; N, 7.78.

3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid.

A mixture of intermediate 26, ethyl3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(2.93 g, 8.2 mmol) and LiOH.H₂O (0.84 g, 20 mmol) in 4:1ethanol/tetrahydrofuran (50 mL) was stirred for 2 h at ambienttemperature then concentrated under vacuum. The resulting yellow residuewas treated with 1N HCl (25 mL) providing a precipitate that wasfiltered and dried under vacuum to yield the title compound as a whitepowder (2.68 g, 99% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.54–7.48(2H, m), 7.37–7.27 (3H, m), 5.44 (2H, s), 4.05–3.93 (4H, m), 1.60 (6H,s).). HRMS (M+H) calcd for C₁₇H₁₉N₂O₅: 331.1294; found: 331.1308. Analcalcd for C₁₇H₁₈N₂O₅: C, 61.81; H, 5.49; N, 8.48; found: C, 61.84; H,5.36; N, 8.25.

2-Ethyl-2-hydroxybutanenitrile.

To a solution of potassium phosphate monobasic (140 g, 1.11 mole) inwater (250 mL) was added 3-pentanone (75.8 g, 0.88 mole), followed by asolution of sodium cyanide (54 g, 1.10 mole) in water (250 mL), and theresulting mixture stirred for 3 hours. The mixture was extracted withdiethyl ether (1×250 mL, then 2×100 mL) and the combined ether layerswashed with 1.0 N HCl (200 mL). The ether solution was dried (Na₂SO₄),filtered, and concentrated in-vacuo. The crude product was purified byvacuum distillation (bp 87° C., 10 mmHg) to give the title compound(72.4 g, 3% yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.71(1H, s), 1.82 (2H, q, J=7.5 Hz), 1.76 (2H, q, J=7.5 Hz), 1.10 (6H, t,J=7.5 Hz). ¹³C NMR (500 MHz, CDCl₃) δ ppm: 121.21, 73.53, 32.81, 8.27.

2-(2-Chloroethoxy)-2-ethylbutanenitrile.

Zinc chloride (68.1 g, 0.5 mol) was fused under vacuum as described inthe procedure for the synthesis of intermediate 23. The molten zinc wascooled and the evacuated flask was flushed with nitrogen. The flask wasloaded with intermediate 28, 2-ethyl-2-hydroxybutanenitrile, (40.3 g,0.5 mol) and 2-chloroethanol (50.5 mL, 0.75 mmol) then stirred at 60° C.for 20 hours. The reaction mixture was diluted with water (250 mL) andextracted with dichloromethane (1×250 mL, 4×100 mL). The combinedorganic layers were dried (sodium sulfate), filtered, and concentratedin-vacuo. The crude product was purified by vacuum distillation (bp 83°C., 10 mmHg) to give the title compound (52 g) containing unreactedintermediate 28. ¹H NMR (500 MHz, CDCl₃) δ ppm: 3.82 (2H, t, J=5.8 Hz),3.64 (2H, t, J=5.8 Hz), 1.83 (4H, J=7.3 Hz), 1.03 (6H, t, J=7.6 Hz).

Diethyl 2-(2,2-diethyl-3-iminomorpholinooxy)but-2-enedioate.

A solution of the product mixture obtained in the synthesis ofintermediate 29, 2-(2-chloroethoxy)-2-ethylbutanenitrile, (0.171 mol) inabsolute ethanol (150 mL) was added dropwise to a solution ofhydroxylamine (50% aqueous solution, 33.8 mL, 0.51 mol), sodiumcarbonate (9.1 g, 0.086 mol) and sodium iodide (2.55 g, 0.017 mol) over15 minutes. The mixture was heated at 80° C. for 3 hours. The reactionwas then concentrated to a thick paste and azeotroped under vacuum withethanol/water (1:1, 100 μL), water (100 μL) and finally ethanol (100mL). The residue was taken up in ethanol/water (1:1, 160 mL), cooled (0°C.), and treated with diethyl acetylenedicarboxylate (30.1 mL, 0.188mol). The reaction was stirred at room temperature for 2 hours, thendiluted with water (200 mL) and ethyl acetate (200 mL). The organiclayer was separated, washed with water (200 mL) and brine (100 mL), thendried (sodium sulfate), filtered and concentrated in-vacuo. The crudeproduct was purified by column chromatography over silica gel, elutingwith 10% to 40% ethyl acetate in hexanes to afford the title compound(25.7 g) as a yellow oil.

Ethyl9,9-diethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.

A solution of intermediate 30, diethyl2-(2,2-diethyl-3-iminomorpholinooxy)but-2-enedioate, (25.7 g) in1,2,4-trimethylbenzene (100 mL) was heated at reflux (180° C.) for 16hours. The solvent was then removed in vacuo and the resulting oilplaced in a freezer until crystal formation began. The oil-crystalmixture was triturated with diethyl ether (50 mL) and the solid wascollected by filtration, washing with a small volume of ether to providethe title compound (9.02 g). A second crop (1.62 g) was obtained fromthe filtrate. ¹H NMR (500 MHz, CDCl₃) δ ppm: 10.54 (1H, s), 4.44 (2H, q,J=7.0 Hz), 4.00 (4H, m), 2.00 (2H, m), 1.92 (2H, m), 1.42 (3H, t, J=7.0Hz), 0.85 (6H, t, J=7.3 Hz). ¹³C NMR (500 MHz, CDCl₃) δ ppm: 169.53,157.82, 151.40, 147.58, 125.35, 87.27, 62.62, 58.35, 43.24, 31.06,14.17, 7.79. HRMS [M+H]⁺ calcd for C₁₄H₂₁N₂O₅: 297.14506; found:297.1464.

2-(3-Chloropropoxy)-2-methylpropanenitrle.

Zinc chloride (68.1 g, 0.5 mol) was fused using the procedure describedfor the synthesis of intermediate 23,2-(2-chloroethoxy)-2-methylpropanenitrile. The molten zinc was cooledand the flask flushed with nitrogen. The flask was loaded with acetonecyanohydrin (46 mL, 0.5 mol) and 3-chloropropanol (64 mL, 0.75 mmol) andthe reaction mixture stirred at 60° C. for 30 hours. The mixture wasthen diluted with water (200 mL) and extracted with dichloromethane(1×200 mL and 3×100 mL). The combined organic layers were dried (sodiumsulfate), filtered, and concentrated in-vacuo. The crude product waspurified by vacuum distillation (bp 78–84° C., 10 mmHg) to give thetitle compound (41 g) as a 2:1 mixture with residual 3-chloropropanol.¹H NMR (500 MHz, CDCl₃) δ ppm: 3.72 (2H, t, J=5.8 Hz), 3.63 (2H, t,J=6.4 Hz), 2.04 (2H, m), 1.57 (6H, br s).

Ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate.

A solution of intermediate 32, 2-(3-chloropropoxy)-2-methylpropanenitrle(0.186 mol) in absolute ethanol (40 mL) was added dropwise to a cold (0°C.) solution of hydroxylamine (50% aqueous solution, 17 mL, 0.278 mol),20 mL H₂O, sodium carbonate (9.91 g, 0.093 mol) and sodium iodide (2.80g, 0.019 mol) over 15 minutes. (In an alternative procedure, sodiumcarbonate was omitted from the mixture). The mixture was stirred at roomtemperature for 30 min, then additional hydroxylamine (17 mL, 0.278 mol)was added. The reaction was then heated at 80° C. for 16 hours. Themixture was concentrated to a thick paste which was azeotroped undervacuum with ethanol/water (1:1, 100 mL). The resulting residue was takenup in ethanol/water (1:1, 200 mL), cooled (0° C.), and treated withdiethyl acetylenedicarboxylate (30.1 mL, 0.188 mol) by dropwise additionover 10 min. The reaction was allowed to stir at room temperature for2.5 hours, then diluted with water (300 mL) and ethyl acetate (300 mL).The separated organic layer was washed with water (100 mL) and brine(100 mL), then dried (sodium sulfate), filtered and concentratedin-vacuo. The crude product was purified by silica gel columnchromatography, eluting with 10% to 40% ethyl acetate in hexanes, togive 21.2 g of a yellow oil. A solution of this oil (15.6 g) in1,2,4-trimethylbenzene (300 mL) was heated at reflux (180° C.) for 2.5hours after which the solvent was removed in-vacuo. The resulting oilwas taken up in ethyl acetate (300 mL) and extracted with saturatedaqueous sodium bicarbonate (1×200 mL, then 4×100 mL). The combinedaqueous layers were acidified to pH 1–2 using 6 N HCl then extractedwith ethyl acetate (3×150 mL). The organic extracts were dried (sodiumsulfate), filtered, then concentrated in vacuo. The resulting oil wastriturated with diethyl ether (50 mL) and the resulting solid collectedby filtration and washed with a small volume of ether to afford thetitle compound (2.05 g). A second crop (0.70 g) was obtained from thefiltrate. ¹H NMR (500 MHz, CDCl₃) δ ppm: 10.83 (1H, br), 10.02 (1H, br),4.46 (2H, q, J=7.0 Hz), 3.66 (2H, t, J=6.1 Hz, 3.58 (2H, t, J=5.8 Hz),2.06 (2H, m), 1.55 (6H, s), 1.44 (3H, t, J=7.0 Hz).

Ethyl3-(benzoyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylate.

A solution of intermediate 33, ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(0.064 g, 0.2 mmol) in pyridine (1 mL) was treated with benzoicanhydride (0.047 g, 0.2 mmol) and stirred for 1 hr at 60° C. The solventwas removed and the residue taken up in N,N-dimethylformamide (1 mL) andtreated with potassium carbonate (0.036 g, 0.2 mmol). The mixture wasstirred for 1 hr at 80° C., and solvent was removed to give the titlecompound.

3-(Benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylicacid.

A suspension of intermediate 33, ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(0.205 g, 0.64 mmol) and anhydrous potassium carbonate (0.361 g, 2.6mmol) in anhydrous dimethylformamide (4 mL) was stirred at 60° C. for 5hours. The reaction mixture was treated with benzyl bromide (0.122 g,0.71 mmol) and stirred for 16 hours. Following this, 2 mL of H₂O wasadded and the mixture stirred for an additional 24 hours. Solvent wasremoved by rotary evaporator and the resulting residue suspended in 0.5N hydrochloric acid (16 mL). The crude product was extracted with ethylacetate (2×15 mL), then dried (sodium sulfate), filtered, andconcentrated to dryness by rotary evaporator to give 0.299 g(Yield>100%) of the title compound as a solid. LC/MS [M+H]⁺=345.21.

3-Hydroxy-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylate.

A solution of intermediate 33, ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(7.01 g, 22 mmol) and anhydrous potassium carbonate (9.12 g, 66 mmol) inanhydrous dimethylformamide (50 mL) was stirred at 80° C. for 20 hours.Solvent was removed by rotary evaporator and the residue, dissolved inwater (50 mL), was brought to pH 1 using 6.0 N HCl. The solution wasextracted with ethyl acetate (4×25 mL). The combined organic layers weredried (sodium sulfate) and filtered. The solvent was removed by rotaryevaporator to give the title compound (5.53 g, Yield 89%) as a brownsolid: ¹H NMR (500 MHz, CDCl₃) δ ppm 10.49 (1H, s), 4.56 (2H, br), 4.43(2H, q, J=7.2 Hz), 3.69 (2H, t, J=6.4 Hz), 1.93–1.99 (2H, m), 1.61 (6H,s), 1.42 (3H, t, J=7.2 Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm 169.33,158.30, 153.39, 148.73, 124.45, 82.85, 62.60, 60.71, 38.79, 27.67,27.35, 14.15; HRMS (ESI) calcd for C₁₃H₁₉N₂O₅ (M+H) 283.1294, found283.1305.

(4-Fluoronaphthalen-1-yl)methanamine hydrochloride.

A solution of 1-cyano-4-fluoronapthalene (1.05 g, 6.12 mmol) and 1.5 mLof HCl (aq.) in absolute ethanol (50 mL) was stirred under a hydrogenatmosphere (balloon) with 10% palladium on carbon (0.20 g) for 16 hours.The catalyst was removed by filtration through Celite, and the filtrateconcentrated under vacuum. The resulting solid was triturated with etherand collected by filtration to give the title compound (0.575 g, 44%yield) as an off white solid.

Methyl 2-(aminomethyl)-5-fluorobenzoate trifluoroacetic acid salt.

Methyl 2-((tert-butoxycarbonyl)methyl)-5-fluorobenzoate, preparedaccording to literature methods, was treated with trifluoroacetic acidto provide the title compound. Yield 100%; ¹H NMR (300 MHz, DMSO-d6) δppm: 3.89 (3H, s) 4.32 (2H, q, J=5.61 Hz) 7.51–7.71 (2H, m) 7.78 (1H,dd, J=9.33, 2.38 Hz) 8.13 (2H, brs); LC/MS m/z 184 (M+H)

2-Aminomethyl-5-fluoro-N-methyl-benzamide trifluoroacetic acid salt.

To a solution of tert-butyl 4-fluoro-2-(methylcarbamoyl)benzylcarbamate(7.70 g, 27.3 mmol; prepared from 2-bromo-5-fluorobenzoic acid usingliterature methods) in CH₂Cl₂ (100 mL) was added CF₃CO₂H (25 mL) and themixture stirred at room temperature for 15 min. This was concentrated invacuo and the residue triturated with diethyl ether to obtain 8.0 g(Yield 99%) of the title compound as a white powder. ¹H NMR (300 MHz,D₂O) δ ppm: 2.93 (3H, s) 4.20 (2H, s) 7.35 (1H, dt, J=8.5, 3 Hz) 7.42(1H, dd, J=9.0, 2.7 Hz) 7.57 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 183(M+H).

2-(Aminomethyl)-N-cyclopropyl-5-fluorobenzamide trifluoroacetic acidsalt.

A solution of tert-butyl2-(cyclopropylcarbamoyl)-4-fluorobenzylcarbamate (130 mg, 0.42 mmol)prepared according to literature methods, in CH₂Cl₂ (5 mL) was stirredwith trifluoroacetic acid (3 mL) at room temperature for 10 min, thenconcentrated in vacuo to give 140 mg (Yield 100%) of the title compoundas a foam: ¹H NMR (DMSO-d6, 300 MHz) δ ppm: 0.62 (2H, m, CH₂), 0.73 (2H,m, CH₂), 2.86 (1H, m, CH), 4.02–4.07 (2H, ABq, NCH₂), 7.46 (2H, m,Ar-Hs), 7.58 (1H, m, Ar—H), 8.11 (3H, br, NH3), 8.81 (1H, d, J=4.4 Hz,NH); LC/MS m/z 209 (M+H).

(5-Fluoro-2-methylphenyl)(morpholino)methanone.

To a solution of morpholine (870 mg, 10 mmol) and triethylamine (1.1 g,10.8 mmol) in CH₂Cl₂ (15 mL) was added a solution of5-fluoro-2-methylbenzoyl chloride (1.72 g, 10 mmol) in CH₂Cl₂ (5 mL),dropwise, and the mixture stirred for 15 min. The mixture was thenwashed with water, and the organic phase dried (MgSO₄), filtered, andconcentrated to obtain 2.19 g (Yield 98%) of the title compound as asolid: ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.27 (3H, s) 3.24 (2H, d, J=4 Hz)3.58 (2H, s) 3.79 (4H, dd, J=18, 3.8 Hz) 6.88 (1H, dd, J=8.2, 2.8 Hz)6.92–7.05 (1H, m) 7.18 (1H, dd, J=8.4, 5.3 Hz).

(2-(Bromomethyl)-5-fluorophenyl)(morpholino)methanone.

A mixture of intermediate 41,(5-fluoro-2-methylphenyl)(morpholino)methanone, (2.1 g, 9.5 mmol) andN-bromosuccinimide (2.0 g, 11 mmol) in CCl₄ (30 mL) was heated atreflux. To this mixture was added benzoylperoxide (242 mg, 1 mmol) andthe mixture heated at reflux for 2 hrs. After cooling, the insolublematerials were filtered and the filtrate purified by columnchromatography (SiO₂, 0–10% ether in CH₂Cl₂) to give 1.1 g (Yield 38%)of the title compound as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ ppm:3.31 (2H, t, J=4.94 Hz) 3.55–4.02 (6H, m) 4.56 (2H, dd, J=128.81, 9.51Hz) 6.89 (1 H, dd, J=8.23, 2.74 Hz) 6.96–7.12 (1H, m) 7.33–7.49 (1H, m);LC/MS m/z 302 (M+H).

(2-(Azidomethyl)-5-fluorophenyl)(morpholino)methanone.

To a solution of intermediate 42,(2-(bromomethyl)-5-fluorophenyl)(morpholino)methanone, (1.0 g, 3.32mmol) in dimethylformamide (10 mL) was added sodium azide (230 mg, 3.5mmol) and the mixture stirred under a nitrogen atmosphere for 1 h. Thesolvent was evaporated in vacuo, and the residue dissolved in CH₂Cl₂,then washed with water. The organic phase was dried (Na₂SO₄), filtered,concentrated, and the residue purified by column chromatography (SiO₂,CH₂Cl₂) to provide 770 mg (Yield 88%) of the title compound as an oil:¹H NMR (300 MHz, CDCl₃) δ ppm: 3.27 (2H, s) 3.51–3.65 (2H, m) 3.66–3.97(4H, m) 4.38 (2H, brs) 6.92 (1H, dd, J=8.2, 2.7 Hz) 7.07 (1H, dt, J=8.5,3 Hz) 7.34 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 265 (M+H).

(2-(Aminomethyl)-5-fluorophenyl)(morpholino)methanone hydrochloride.

To a solution of intermediate 43,(2-(azidomethyl)-5-fluorophenyl)(morpholino)methanone, (770 mg, 2.92mmol,) in ethanol (20 mL) was added 4N HCl (1 mL) and 10% Pd—C (100 mg),and the mixture hydrogenated at 1 atm of H₂ for 3 hrs. The catalyst wasremoved by filtration and the filtrate concentrated. The residue waspurified by C18 reverse phase silica gel column chromatography (YMC ODS,0–5% CH₃CN/H₂O) to obtain 350 mg (Yield 44%) of the title compound,(2-(aminomethyl)-5-fluorophenyl)(morpholino)-methanone hydrochloride asa white powder: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 3.0–4.0 (8H, m), 3.78(2H, t, J=5 Hz), 7.32 (1H, dd, J=8.8, 2.6 Hz), 7.35–7.44 (1H, t, J=8.5,3 Hz), 7.75 (1H, dd, J=8.8, 5.5 Hz); LC/MS m/z 239 (M+H).

5-Fluoro-2,N,N-trimethyl-benzenesulfonamide.

To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20mmol) in tetrahydrofuran (25 mL) was added, dropwise, a solution ofdimethylamine in tetrahydrofuran (2M, 25 mL, 50 mmol) over 15 min. andthe mixture stirred for 5 min. The insoluble materials were filtered andthe filtrate concentrated. The residue was purified by columnchromatography (SiO₂, 5% ether in CH₂Cl₂) to provide 4.3 g (Yield 90%)of the title compound as a clear oil: ¹H NMR (500 MHz, CDCl₃) δ ppm:2.57 (3H, s) 2.82 (3H, s) 2.82 (3H, s) 7.12–7.18 (1H, m) 7.28 (1H, dd,J=8.2, 5.5 Hz) 7.59 (1H, dd, J=8.2, 2.1 Hz); LC/MC m/z 218 (M+H).

2-Bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide.

Under nitrogen, a mixture of intermediate 45,5-fluoro-2,N,N-trimethyl-benzenesulfonamide, (435 mg, 2.0 mmol) andN-bromosuccinimide (391 mg, 2.2 mmol) in CCl₄ (20 mL) was stirred at80–90° C. for 5 min. To this mixture was added2,2′-azobisisobutyronitrile (AIBN, 100 mg) and stirring continued at80–90° C. for 30 min. After cooling, the insoluble precipitates werefiltered and the filtrate concentrated and purified by columnchromatography (SiO₂, CH₂Cl₂) to provide 440 mg (Yield 74%) of the titlecompound; ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.87 (6H, s) 4.86 (2H, s) 7.28(1H, dd, J=8.55, 2.75 Hz) 7.61–7.65 (2H, m); LC/MC m/z 296/298 (M+H).

2-Azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide.

A mixture of intermediate 46,2-bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (880 mg, 2.97mmol) and sodium azide (200 mg, 3 mmol) in dimethylformamide (4 mL) wasstirred at 55–60° C. for 30 min after which the solvent was removed invacuo. The residue was partitioned between CH₂Cl₂ and water, and theorganic phase was washed with water, dried (Na₂SO₄), filtered andconcentrated to provide 670 mg (Yield 87%) of the title compound as ayellow oil; ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.84 (6H, s) 4.78 (2H, s)7.29–7.34 (1H, m) 7.59–7.64 (2H, m).

2-(Aminomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide.

To a solution of intermediate 47,2-azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (660 mg, 2.6mmol) in tetrahydrofuran (10 mL) and water (2 mL) was addedtriphenylphosphine (740 mg, 2.8 mmol), and the mixture stirred undernitrogen for 1 hr. The tetrahydrofuran was evaporated in vacuo and amixture of the residue and 6N HCl (3 mL) in MeOH (5 mL) was heated at80° C. for 20 hrs. This was washed with CH₂Cl₂, and the aqueous phasebasified with dilute NH₄OH and extracted with CH₂Cl₂. The organicextract was dried (Na₂SO₄), filtered and concentrated to provide 210 mg(0.91 mmol, Yield 35%) of the title compound; ¹H NMR (500 MHz, CDCl₃) δppm: 2.84 (6H, s) 4.10 (2H, s) 7.23–7.29 (1H, m) 7.53–7.60 (2H, m);LC/MS m/z 233 (M+H).

5-Fluoro-2,N-dimethyl-benzenesulfonamide.

To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20mmol) in acetone (20 mL) was added a 40% aqueous solution of methylamine(4.5 mL, 60 mmol) under nitrogen and the mixture stirred for 5 min.Acetone was removed in vacuo and the aqueous residue extracted withCH₂Cl₂. The CH₂Cl₂ extract was dried (Na₂SO₄), filtered, concentratedand the residue purified by column chromatography (SiO₂, 10% ether inCH₂Cl₂) to provide 3.9 g (19.2 mmol, Yield 96%) of the title compound asa white solid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.59 (3H, s), 2.67 (3H, d,J=5.5 Hz), 4.41 (1H, brs), 7.13–7.20 (1H, m), 7.29 (1H, dd, J=8.2, 5.5Hz), 7.69 (1H, J=8.6, 2.1 Hz); LC/MS m/z 204 (M+H).

2-Bromomethyl-5-fluoro-N-methyl-benzenesulfonamide.

The title compound can be prepared from intermediate 49,5-fluoro-2,N-dimethyl-benzenesulfonamide, according to the methoddescribed for intermediate 46 and purified by column chromatography(SiO₂, 5% ether/CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃) δ ppm: 2.64 (3H, d,J=5.19 Hz) 4.91 (1H, d, J=3.66 Hz) 4.98 (2H, s) 7.26–7.30 (1H, m) 7.54(1H, dd, J=8.6, 5.2 Hz) 7.73 (1H, dd, J=8.4, 2.6 Hz); LC/MS m/z 282/284.

2-Azidomethyl-5-fluoro-N-methyl-benzenesulfonamide.

The title compound can be prepared from intermediate 50,2-bromomethyl-5-fluoro-N-methyl-benzenesulfonamide, according to themethod described for intermediate 47 and purified by columnchromatography (SiO₂, 5% ether-CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃) δ ppm:2.65 (3H, d, J=5.19 Hz) 4.81 (2H, s) 4.86 (1H, d, J=4.6 Hz) 7.27–7.33(1H, m) 7.49 (1H, dd, J=8.2, 5.2 Hz) 7.76 (1H, dd, J=8.2, 2.8 Hz).

2-(Aminomethyl)-5-fluoro-N-methylbenzenesulfonamide hydrochloride.

To a solution of intermediate 51,2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide, (560 mg, 2.3 mmol)in ethanol (10 mL) was added 6N HCl (1 mL) and 10% Pd—C (100 mg) and themixture hydrogenated with 1 atm of H₂ for 14 hrs. The catalyst wasremoved by filtration through Celite and the filtrate concentrated invacuo to provide 630 mg (Yield>100%) of the title compound. ¹H NMR (500MHz, DMSO-D6) δ ppm: 4.36 (2H, d, J=5.2 Hz) 7.63–7.70 (2H, m) 7.77–7.83(1H, m) 8.11 (1H, d, J=4.9 Hz) 8.41 (3H, s); LC/MS m/z 219 (M+H).

5-Fluoro-2-methyl-benzenesulfonamide.

To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20mmol) in acetone (20 mL) was added, dropwise, concentrated NH₄OH (3 mL)and the resulting mixture stirred for 5 min. Acetone was removed invacuo and the precipitates were filtered, washed thoroughly with waterand dried in vacuo to provide 3.7 g (Yield 98%) of the title compound asa white solid; ¹H NMR (500 MHz, DMSO-D6) δ ppm: 2.55 (3H, s) 7.33–7.40(1H, m) 7.40–7.46 (1H, m) 7.54 (2H, s) 7.59 (1H, dd, J=9.2, 2.7 Hz);LC/MS m/z 190 (M+H).

2-Bromomethyl-5-fluoro-benzenesulfonamide.

The title compound can be prepared from intermediate 53,5-fluoro-2-methyl-benzenesulfonamide, according to the method describedfor intermediate 46, and purified by column chromatography (SiO₂, 5%ether/CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃) δ ppm: 5.01 (2H, s) 5.16 (2H,brs) 7.25–7.31 (1H, m) 7.53 (1H, dd, J=8.5, 5.2 Hz) 7.80 (1H, dd, J=8.5,2.7 Hz) LC/MS m/z 268/270 (M+H).

2-Azidomethyl-5-fluoro-N-methyl-benzenesulfonamide.

The title compound can be prepared from intermediate 54,2-bromomethyl-5-fluoro-benzenesulfonamide, according to the methoddescribed for the preparation of intermediate 47. ¹H NMR (300 MHz,CDCl₃) δ ppm: 4.82 (2H, s) 5.18 (2H, s) 7.27 (1H, m) 7.45 (1H, dd,J=8.4, 5.5 Hz) 7.79 (1H, dd, J=8.4, 2.6 Hz). LC/MS m/z 253 (M+Na).

2-(Aminomethyl)-S-fluorobenzenesulfonamide hydrochloride.

The title compound can be prepared from intermediate 55,2-azidomethyl-5-fluoro-N-methyl-benzenesulfonamide, according to themethod described for the preparation of intermediate 48. ¹H NMR (500MHz, DMSO-D6) δ ppm: 4.05 (2H, s) 5.05 (3H, br) 7.44 (1H, dt, J=8.5, 3Hz) 7.58 (1H, dd, J=9.2, 2.7 Hz) 7.66 (1H, dd, J=8.5, 5.5 Hz). LC/MS m/z205 (M+H).

5-(2-Bromo-5-fluoro-phenyl)-2-methyl-2H-tetrazole.

A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12mmol), iodomethane (1.12 g, 10 mmol) and potassium carbonate (1.5 g) indimethylformamide (5 mL) was stirred at room temperature for 16 hrs,then concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, CH₂Cl₂) to provide 650 mg (Yield 61%) of the titlecompound as a white powder. ¹H NMR (500 MHz, CDCl₃) δ ppm: 4.45 (3H, s)7.03–7.11 (1H, m) 7.63 (1H, dd, J=8.9, 3.1 Hz) 7.69 (1H, dd, J=8.9, 5.5Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm: 39.86, 116.28, 118.66, 118.76,130.13, 135.73, 161.74, 163.53; LC/MS m/z 257/259.

4-Fluoro-2-(2-methyl-2H-tetrazol-5-yl)-benzonitrile.

A mixture of intermediate 57,5-(2-bromo-5-fluoro-phenyl)-2-methyl-2H-tetrazole (650 mg, 2.53 mmol)and CuCN (224 mg, 2.5 mmol) in dimethylformamide (4 mL) was placed in asealed tube and heated at 100–110° C. for 20 hrs. After cooling, theinsoluble material was filtered, and the filtrate concentrated in vacuo.The residue was dissolved in CH₂Cl₂, washed with aq. 4N HCl and dil.NH₄OH, then dried (MgSO₄), filtered, and concentrated. The residualsolid was purified by column chromatography (SiO₂, CH₂Cl₂) to obtain 375mg (Yield 73%) of the title compound as an off-white solid; ¹H NMR (500MHz, CDCl₃) δ ppm: 4.48 (3H, s) 7.29 (1H, dd, J=7.6, 2.8 Hz) 7.85 (1H,dd, J=8.6, 5.2 Hz) 8.00 (1H, dd, J=9.0, 2.6 Hz); LC/MS m/z 204.

(4-Fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)methanamine hydrochloride.

A solution of intermediate 58,4-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-benzonitrile, (330 mg, 1.62 mmol)in ethanol (15 mL) was mixed with 6N HCl (1 mL) and 10% Pd—C (200 mg)under nitrogen. The mixture was then stirred under hydrogen (1 atm) for3 hrs. After removing the catalyst, the filtrate was concentrated invacuo to provide 360 mg (Yield 91%) of the title compound as anoff-white solid; ¹H NMR (500 MHz, DMSO-D6) δ ppm: 4.42 (2H, d, J=2.75Hz) 4.49 (3H, s) 7.48–7.56 (1m) 7.78 (1H, dd, J=8.7, 5.7 Hz) 7.86 (1H,dd, J=9.8, 2.8 Hz) 8.45 (3H, s); LC/MS m/z 208.

5-(2-Bromo-5-fluoro-phenyl)-1-methyl-2H-tetrazole.

A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12mmol), iodomethane (1.12 g, 10 mmol) and potassium carbonate (1.5 g) indimethylformamide (5 mL) was stirred at room temperature for 16 hrs,then concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, CH₂Cl₂) to provide 350 mg (Yield 33%) of the titlecompound as white crystals. ¹H NMR (500 MHz, CDCl₃) δ ppm: 4.00 (3H, s)7.18–7.25 (2H, m) 7.72 (1H, dd, J=8.4, 5.0 Hz); ¹³C NMR (126 MHz, CDCl₃)δ ppm: 34.59, 117.73, 119.58, 120.43, 127.57, 135.11, 153.43, 161.69.LC/MS m/z 257/259.

4-Fluoro-2-(1-methyl-2H-tetrazol-5-yl)-benzonitrile.

¹H NMR (300 MHz, CDCl₃) δ ppm: 4.13 (3H, s) 7.38–7.49 (2H, m) 7.86–7.97(1H, m); LC/MS m/z 204 (M+H).

(4-Fluoro-2-(1-methyl-2H-tetrazol-5-yl)phenyl)methanamine hydrochloride.

¹H NMR (500 MHz, DMSO-D6) δ ppm: 4.05 (2H, s) 4.09 (3H, s) 7.58–7.67(1H, m) 7.77 (1H, dd, J=9.3, 2.6 Hz) 7.87 (1H, dd, J=8.7, 5.7 Hz) 8.38(3H, s); LC/MS m/z 208.

3-m-Tolyl-3-trifluoromethyl-3H-diazirine.

To a cold stirring solution of 3-m-tolyl-3-trifluoromethyl-diaziridine(2.0 g, 10 mmol. prepared using the methods described inDoucet-Personeni C. et al., J. Med. Chem., 2001, 44, 3203 and Nassal, M.Liebigs Ann. Chem. 1983, 1510–1523 or in Stromgaard, K et al., J. Med.Chem., 2002, 45, 4038–46) in ethanol (20 mL) was added triethylamine(1.5 g, 15 mmol). To this mixture was added tert-butyl hypochlorite(3.25 g, 30 mmol), and the mixture stirred for 5 min. This mixture waspoured into 10% aqueous sodium sulfite (100 mL), and extracted withether. The ether extract was washed with brine, dried (MgSO₄), filteredand concentrated. The residue was purified by column chromatography(SiO₂, pentane) to provide 1.6 g (Yield 80%) of the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm: 2.33 (3H, s) 6.90–7.03 (2H, m) 7.15–7.31(2H, m).

3-(3-Bromomethyl-phenyl)-3-trifluoromethyl-3H-diazirine.

To a solution of intermediate 63,3-m-tolyl-3-trifluoromethyl-3H-diazirine, (200 mg, 1 mmol) in CCl₄ (4mL) was added N-bromosuccinimide (200 mg, 1.1 mmol, re-crystallized fromwater), and the stirred mixture heated at 85° C. To this was added AIBN(50 mg) and the mixture heated at reflux for an additional 2.5 hrs.After cooling, the mixture was purified by column chromatography (SiO₂,pentane) to provide 150 mg (Yield 54%) of the title compound as a clearoil. ¹H NMR (300 MHz, CDCl₃) δ ppm: 4.42 (2H, s) 7.10–7.17 (2H, m)7.31–7.45 (2H, m).

2-[3-(3-Trifluoromethyl-diaziridin-3-yl)-benzyl]-isoindole-1,3-dione.

A mixture of intermediate 64,3-(3-bromomethyl-phenyl)-3-trifluoromethyl-3H-diazirine, (140 mg, 0.5mmol) and potassium phthalimide (95 mg, 0.5 mmol) in dimethylformamide(1.5 mL) was stirred at room temperature for 3 hrs. Dimethylformamidewas removed in vacuo. The residue was extracted with CH₂Cl₂, washed withwater, then dried (Na₂SO₄), filtered, and concentrated. The resultingresidue was purified by column chromatography (SiO₂, 1:1 CH₂Cl₂/pentane)to provide 140 mg (Yield 82%) of the title compound as a solid; ¹H NMR(300 MHz, CDCl₃) δ ppm: 4.80 (2H, s) 7.09–7.21 (2H, m) 7.32 (1H, t,J=7.9 Hz) 7.41–7.49 (2H, m) 7.66–7.71 (2H, m) 7.81–7.85 (2H, m); LC/MSm/z 346 (M+H).

(3-(3-(Trifluoromethyl)diaziridin-3-yl)phenyl)methanamine.

A stirred solution of intermediate 65,2-[3-(3-trifluoromethyl-diaziridin-3-yl)-benzyl]-isoindole-1,3-dione,(150 mg, 0.43 mmol) in ethanol (2 mL) was treated with hydrazine hydrate(0.4 mL) at room temperature and the solution stirred for 3.5 hrs. Afterremoving ethanol in vacuo, the residue was partitioned between CH₂Cl₂and water. The aqueous phase was acidified with dilute HCl, and washedwith CH₂Cl₂. The aqueous phase was basified with dilute NaOH, andextracted with CH₂Cl₂. The organic extract was dried (MgSO₄), filtered,and concentrated to obtain 50 mg (Yield 54%) of(3-(3-(trifluoromethyl)diaziridin-3-yl)phenyl)methanamine and(3-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanamine as a 1:1mixture; ¹H NMR (300 MHz, CDCl₃) δ ppm: 3.85 (2H, s) 3.88 (2H, s) 7.08(2H, s) 7.31–7.40 (4H, m) 7.43–7.50 (1H, m, J=6.2 Hz) 7.54 (1H, s);LC/MS m/z 216 (M+H for diazirine) and 218 (M+H for diaziridine).

Intermediates 67–68

To a solution of 2,4-difluorobenzonitrile (10 g, 72 mmol) dissolved intetrahydrofuran (20 mL), and dimethylformamide (40 mL) was added1,2,4-triazole sodium salt (6.3 g, 70 mmol) and the mixture stirred at90° C. for 3 h after which the mixture was filtered and the solventremoved. The resulting residue was adsorbed onto silica gel andintermediates 67 and 68 separated by flash chromatography, eluting with0% to 30% ethyl acetate/hexanes.

4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile.

Colorless needles (2.46 g, 18% yield) ¹H NMR (500 MHz, CDCl₃) δ: 8.89(1H, s), 8.19 (1H, s), 7.85 (1H, dd, J=8.7, 5.6 Hz), 7.60 (1H, dd,J=8.8, 2.4 Hz), 7.28–7.24 (1H, m). LCMS (M+H) calcd for C₉H₆N₄F: 189.05;found: 189.13.

4-(1H-1,2,4-Triazol-1-yl)-2-fluorobenzonitrile.

White solid (0.746 g, 6% yield) ¹H NMR (500 MHz, CDCl₃) δ: 8.66 (1H, s),8.15 (1H, s), 7.79 (1H, dd, J=8.5, 6.7 Hz), 7.69 (1H, dd, J=9.5, 1.8Hz), 7.65–7.63 (1H, m). LCMS (M+H) calcd for C₉H₆N₄F: 189.05; found:189.13.

(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride).

Intermediate 67, 4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile, (2.46g, 13.13 mmol) was dissolved in hot ethanol (150 mL). To this was added1N HCl (15 mL) followed by 10% Pd—C (200 mg). The mixture was treatedwith H₂ at 55 psi for 4 h in a Parr shaker then filtered over Celite andthe solvent removed under reduced pressure. The resulting residue waspartitioned between ethyl acetate and water. The aqueous phase wasseparated and lyophilized to afford the title compound as a white powder(2.96 g, 99% yield). ¹H NMR (500 MHz, CD₃OD) δ ppm: 9.51 (1H, s), 8.63(1H, s), 7.85 (1H, dd, J=8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz),7.49 (1H, td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd forC₉H₁₀N₄F: 193.08; found: 193.16.

(2-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride.

The title compound can be prepared from intermediate 68 according to themethod described for the synthesis of intermediate 69. White powder (79%yield). ¹H NMR (500 MHz, CD₃OD) δ ppm: 9.25 (1H, s), 8.46 (1H, s), 7.80(1H, dd, J=8.6, 5.8 Hz), 7.64 (1H, dd, J=8.8, 2.4 Hz), 7.44 (1H, td,J=8.3, 2.6 Hz), 4.17 (2H, s). LCMS (M+H) calcd for C₉H₁₀N₄F: 193.08;found: 193.16.

Intermediates 71–74

Intermediates 71–74 were prepared using the procedure described for thesynthesis of intermediate 67–70.

4-Fluoro-2-morpholinobenzonitrile

¹H NMR (500 MHz, CDCl₃) δ ppm: 7.55 (1H, dd, J=8.5, 6.4 Hz), 6.71 (1H,td, J=8.1, 2.3 Hz), 6.67 (1H, dd, J=11.0, 2.4 Hz), 3.88 (4H, t, J=4.6Hz), 3.22 (4H, t, J=4.6 Hz). LCMS (M+H) calcd for C₁₁H₁₂N₂OF: 207.09;found: 207.19.

4-Morpholino-2-fluorobenzonitrile.

¹H NMR (500 MHz, CDCl₃) δ ppm: 7.42 (1H, dd, J=8.8, 7.6 Hz), 6.63 (1H,dd, J=8.8, 2.4 Hz), 6.56 (1H, dd, J=12.8, 2.4 Hz), 3.84 (4H, t, J=4.9Hz), 3.28 (4H, t, J=4.9 Hz). LCMS (M+H) calcd for C₁₁H₁₂N₂OF: 207.09;found: 207.19.

(4-Fluoro-2-morpholinophenyl)methanamine hydrochloride.

¹H NMR (500 MHz, CDCl₃) δ ppm: 7.54 (1H, t, J=7.3 Hz), 7.20 (1H, dd,J=10.5, 2.0 Hz), 7.05–7.02 (1H, m), 4.28 (2H, s), 3.93 (4H, bs), 3.03(4H, bs). LCMS (M+H) calcd for C₁₁H₁₆N₂OF: 211.12; found: 211.23.

(2-Fluoro-4-morpholinophenyl)methanamine hydrochloride.

¹H NMR (500 MHz, CD₃OD) δ ppm: 7.73 (1H, t, J=8.2 Hz), 7.62 (1H, d,J=7.6 Hz), 7.58 (1H, d, J=8.2 Hz), 4.26 (2H, s), 4.11 (4H, t, J=4.4 Hz),3.65 (4H, t, J=4.4 Hz). LCMS (M+H) calcd for C₁₁H₁₆N₂OF: 211.12; found:211.23.

4-Fluoro-2-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzonitrile.

To a mixture of 2,4-difluorobenzonitrile (10.0 g, 72 mmol) and1,1-dioxo-1λ6-[1,2]thiazin-2-ane (8.84 g, 65.4 mmol) in 1:1tetrahydrofuran/dimethylformamide (40 mL) was added potassium carbonate(9.0 g, 65.4 mmol). The mixture was stirred at 90° C. for 18 h thenfiltered and concentrated. The residue was purified by flashchromatography (SiO₂) eluting with 10%-50% ethyl acetate/hexanesfollowed by recrystallization from hot ethyl acetate/hexane to give thetitle compound as white needles (0.537 g, 3% yield). ¹H NMR (500 MHz,CD₃OD) δ ppm: 7.70 (1H, dd, J=8.8, 5.8 Hz), 7.30 (1H, dd, J=8.8, 2.4Hz), 7.15–7.12 (1H, m), 3.27 (2H, t, J=5.3 Hz), 3.33 (2H, t, J=6.1 Hz),2.40–2.35 (2H, m), 2.05–2.01 (2H, m). LCMS (M+H) calcd for C₁₁H₁₆N₂OF:255.06; found: 255.19.

(4-Fluoro-2-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)phenyl)methanaminehydrochloride.

Intermediate 75,4-fluoro-2-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzonitrile (1.37 g, 5.4mmol) was dissolved in ethanol (120 mL). To this was added 1N HCl (20mL) and a catalytic amount of 10% Pd—C. The mixture was shaken underhydrogen at 55 psi for 4 h then filtered through Celite and concentratedto give the title compound as white solid (1.58 g, 100% yield). ¹H-NMR(300 MHz, CD₃OD) δ ppm: 7.61 (1H, dd, J=8.4, 6.2 Hz), 7.38 (1H, dd,J=9.3, 2.7 Hz), 7.28 (1H, td, J=8.2, 2,7 Hz), 7.26 (2H, dd, J=21.4, 13.7Hz), 3.93–3.84 (1H, m), 3.50–3.41 (3H, m), 2.40–2.31 (2H, m), 2.04–1.96(2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₆N₂O₆FS: 259.087; found: 259.24.

Intermediates 77–78

To a solution of 1H-1,2,3-triazole (3.5 g, 50.7 mmol) in tetrahydrofuran(10 mL) and dimethylformamide (20 mL) was added, portionwise, NaH (1.3g, 51 mmol, 95%). The mixture was stirred at room temp for 30 min.2,4-Difluorobenzonitrile (7.6 g, 55 mmol) was added and the mixturestirred at 85° C. for 3 h. The white mixture was concentrated andpurified by flash chromatography eluting with 0% to 10% ethylacetate/hexanes to give intermediates 77 and 78.

4-Fluoro-2–1,2,3-triazol-2-yl-benzonitrile.

White needles (0.34 g, 3% yield). ¹H-NMR (300 MHz, CDCl₃) δ ppm: 7.92(2H, s), 7.88–7.79 (2H, m), 7.19–7.12 (1H, m). LCMS [M+H]+ calcd forC₉H₆N₄F: 189.05; found: 189.12.

2-Fluoro-4–1,2,3-triazol-2-yl-benzonitrile.

White solid (0.097 g, 1% yield). ¹H-NMR (300 MHz, CDCl₃) δ ppm:8.03–7.95 (2H, m), 7.86 (2H, s), 7.74–7.69 (1H, m).

4-Fluoro-2–1,2,3-triazol-2-yl-benzylamine hydrochloride.

Intermediate 77, 4-fluoro-2–1,2,3-triazol-2-yl-benzonitrile, (0.34 g,1.8 mmol) was dissolved in ethanol (50 mL). 1N HCl (10 mL) was addedalong with a catalytic amount of 10%-Pd—C. The mixture was shaken underH₂ at 55 psi for 4 h after which it was filtered through Celite andconcentrated to give the title compound as the corresponding HCl salt.Yellow solid (0.402 g, 98% yield). ¹H-NMR (500 MHz, CD₃OD) δ ppm: 8.13(2H, s), 7.87 (1H, dd, J=4.9, 2.6 Hz), 7.73 (1H, dd, J=4.9, 2.6 Hz),7.34 (1H, td, J=8.2, 2.7 Hz), 4.35 (2H, s). LCMS [M+H]⁺ calcd forC₉H₁₀N₄F: 193.08; found: 193.16.

(2-Fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)methanamine:

The title compound can be prepared from intermediate 78,2-fluoro-4–1,2,3-triazol-2-yl-benzonitrile, according to the procedureprovide for intermediate 79. ¹H-NMR (300 MHz, CD₃OD) δ ppm: 8.05–7.96(2H, m), 8.00 (2H, s), 7.68 (1H, t, J=8.2 Hz), 4.26 s). LCMS [M+H]⁺calcd for C₉H₁₀N₄F: 193.08; found: 193.14.

Intermediates 81–84

A solution of 2,4-difluorobenzonitrile (7.07 g, 50.8 mmol) and3-methyl-1H-1,2,4-triazole (4.22 g, 50.8 mmol) in N,N-dimethylformamide(45 ml) was treated with powdered anhydrous potassium carbonate (10 g)and the resulting mixture stirred at 22° C. for 18 h. The solid was thenfiltered and the filtrate concentrated in vacuo. The residue was dilutedwith ethyl acetate, washed with water and brine, then dried overanhydrous magnesium sulfate and concentrated. The resulting mixture waspurified by a combination of chromatography on silica gel (elutiongradient of ethyl acetate in hexane) and reversed phase silica gel toyield intermediates 81–84.

4Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile.

White crystals (ethyl acetate-hexane); mp 117–118° C. ¹HNMR 400 MHz(CDCl₃) δ ppm: 2.54 (3H, s, CH₃), 7.24 (1H, m, CH), 7.62 (1H, dd, J=2.5Hz and J=9.1 Hz, CH), 7.84 (1H, dd, J=5.6 Hz and J=8.6 Hz, CH), 8.82(1H, s, CH). Anal. Calcd for C₁₀H₇FN₄: C, 59.40, H, 3.49, N, 27.71;Found: C, 59.25; H, 3.32; N, 27.81.

4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile.

White crystals (ethyl acetate-hexane); mp 120–121° C. ¹HNMR 400 MHz(CDCl₃) δ ppm: 2.56 (3H, s, CH₃), 7.30 (1H, dd, J=2.5 Hz and J=8.1 Hz,CH), 7.39 (1H, m, CH), 7.91 (1H, dd, J=5.5 Hz and J=8.6 Hz, CH), 8.06(1H, s, CH). Anal. Calcd for C₁₀H₇FN₄: C, 59.40, H, 3.49, N, 27.71;Found: C, 59.35; H, 3.70; N, 27.77.

2-Fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile.

White crystals (ethyl acetate-hexane); mp 133–134° C. ¹HNMR 400 MHz(CDCl₃) δ ppm: 2.52 (3H, s, CH₃), 7.61 (1H, dd, J=2 Hz and J=9.1 Hz,CH), 7.67 (1H, dd, J=2 Hz and J=9.6 Hz, CH), 7.79 (1H, dd, J=6.5 Hz andJ=8.6 Hz, CH), 8.56 (1H, s, CH). Anal. Calcd for C₁₀H₇FN₄: C, 59.40; H,3.49; N, 27.71; Found: C, 59.42; H, 3.24; N, 28.41.

2-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile.

White crystals (ethyl acetate-hexane); mp 89–90° C., ¹HNMR 400 MHz(CDCl₃) δ ppm: 2.69 (3H, s, CH₃), 7.49–7.55 (2H, m, 2×CH), 7.83 (1H, dd,J=6.8 Hz and J=8.8 Hz, CH), 8.00 (1H, s, CH). Anal. Calcd for C₁₀H₇FN₄:C, 59.40; H, 3.49; N, 27.71; Found: C, 59.17, H 3.22, N, 28.01.

(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride salt.

Hydrogenation of intermediate 81,4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile, (0.680 g, 3.36mmol) gave 0.720 g (88% yield) of the title hydrochloride salt as awhite solid. ¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.40 (3H, s, CH₃), 4.02 (2H,m, NCH₂), 7.50 (1H, m, CH), 7.62 (1H, dd, J=2.8 Hz and J=9.3 Hz, CH),7.84 (1H, dd, J=6.1 Hz and J=9.1 Hz, CH), 9.00 (1H, s, CH). HRMS (ESI⁺)calculated for C₁₀H₁₂FN₄ [M+H⁺]: 207.1046; found: 207.1047.

(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride salt.

Hydrogenation of intermediate 82,4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile, (0.244 g, 1.20mmol) gave 0.290 g (100% yield) of the title hydrochloride salt as awhite solid. ¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.42 (3H, s, CH₃), 3.78 (2H,m, NCH₂), 7.58 (1H, m, CH), 7.67 (1H, dd, J=2.8 Hz and J=9.3 Hz, CH),7.90 (1H, dd, J=6.0 Hz and J=8.6 Hz, CH), 8.22 (1H, s, CH). HRMS (ESI⁺)calculated for C₁₀H₁₂FN₄ [M+H⁺]: 207.1046; found: 207.1041.

(2-Fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride salt.

Hydrogenation of intermediate 83,2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile, (0.220 g, 1.09mmol) gave 0.260 g (98% yield) of the title hydrochloride salt as awhite solid. ¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.38 (3H, s, CH₃), 4.09 (2H,m, NCH₂), 7.75–7.8 (2H, m, 2×CH), 7.83 (1H, dd, J=2 Hz and J=9 Hz, CH),9.29 (1H, s, CH). MS (ESI⁺) m/e 207 [M+H⁺].

4-Fluoro-2-imidazol-1-yl-benzonitrile.

To a solution of imidazole (4.45 g, 65.4 mmol) in tetrahydrofuran (30mL) and dimethylformamide (10 mL) was added potassium carbonate (9.95 g,72 mmol) and the mixture was stirred for 30 min at room temp. To thiswas added 2,4-difluorobenzonitrile (10.0 g, 72 mmol) and the mixturestirred at 90° C. for 3 h then at room temp for 2 days. The mixture wasfiltered and concentrated and the residue was purified by flashchromatography (SiO₂) eluting with 20% to 70% ethyl acetate/hexane togive the title compound as white needles (1.1 g, 9% yield). ¹H-NMR (500MHz, CDCl₃) δ ppm: 7.94 (1H, s), 7.84 (1H, dd, J=8.7, 5.6 Hz), 7.37 (1H,t, J=8.7, 5.6 Hz), 7.37 (1H, t, J=1.4 Hz), 7.29 (1H, t, J=1.1 Hz),7.27–7.21 (2H, m). LCMS [M+H]⁺ calcd for C₁₀H₇N₃F: 188.058; found:188.12.

(4-Fluoro-2-(1H-imidazo-1-yl)phenyl)methanamine) hydrochloride.

The title compound can be prepared from intermediate 88,4-fluoro-2-imidazol-1-yl-benzonitrile, according to the method providedfor intermediate 79. Yellow solid, ¹H-NMR (500 MHz, CD₃OD) δ ppm: 9.39(1H, s), 7.98 (1H, d, J=1.5 Hz), 7.92–7.89 (2H, m), 7.63–7.59 (2H, m),4.11 (2H, s). LCMS [M+H]⁺ calcd for C₁₀H₁₁N₃F: 192.09; found: 192.15.

1-(2-Cyano-5-fluoro-phenyl)-J H-1,2,4-triazole-3-carboxylic acid methylester.

To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (27 g, 215 mmol)in dimethylformamide (170 mL) was added sodium hydride (5.53 g, 95%, 217mmol) and the mixture was stirred for 30 min. Added to this was2,4-difluorobenzylnitrile (30 g, 217 mmol) and the resulting mixturestirred at room temp for 60 h. The mixture was diluted with water andfiltered to remove solids. The solution was extracted with ethyl acetateand the organic phase was washed with water (3×'s) and brine, then dried(Na₂SO₄) and concentrated. The resulting residue was purified by flashchromatography (SiO₂) eluting with 30% tetrahydrofuran/20% CH₂Cl₂/50%hexane to give the title compound as white needles (5.34 g, 10% yield).¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.92 (1H, s), 7.85 (1H, dd, J=8.8, 5.5Hz), 7.67 (1H, dd, J=8.8, 2,6 Hz), 7.34–7.27 (1H, m), 40.3 (3H, s). LCMS[M+H]⁺ calcd for C₁₁H₈N₄FO₂: 247.06; found: 247.11.

Methyl1-(2-(aminomethyl)-5-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate.

The title compound can be prepared from intermediate 90,1-(2-cyano-5-fluoro-phenyl)-1H-1,2,4-triazole-3-carboxylic acid methylester ¹H-NMR (300 MHz, CD₃OD) δ ppm: 9.15 (1H, s), 7.80 (1H, dd, J=8.8,5.9 Hz), 7.71 (1H, dd, J=8.8, 2.6 Hz), 7.46 (1H, td J=8.2, 2.6 Hz), 4.19(2H, s), 4.03 (3H, s). LCMS [M+H]⁺ calcd for C₁₁H₁₂N₄O₂: 251.09; found:251.17.

3-Fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzonitrile.

To a solution of 1,1-dioxo-1λ6-[1,2]thiazin-2-ane (1.90 g, 14.4 mmol)dissolved in tetrahydrofuran (8 mL) and dimethylformamide (2 mL) wasadded sodium hydride (0.36 g, 95%, 14.4 mmol) and the mixture stirredfor 20 min. To this was added 2,3-difluorobenzonitrile (2.0 g, 14.4mmol) and the mixture stirred at 90° C. for 2 h. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with water and brine then concentrated. The solid residue wastriturated with 1:1 ethyl acetate/hexane to give the title compound as apale brown solid (0.47 g, 13% yield). ¹H-NMR (500 MHz, CDCl₃) δ ppm:7.47–7.45 (1H, m), 7.32–7.36 (2H, m), 4.08–4.02 (1H, m), 3.57 (1H, td,J=13.0, 3,7 Hz), 3.40–3.34 (1H, m), 3.32–3.27 (1H, m), 2.44–2.32 (2HF,m), 2.04–1.97 (2H, m), 1.90–1.84 (1H, m). LCMS [M+H]⁺ calcd forC₁₁H₁₂N₂FO₂S: 255.28; found: 255.13.

3-Fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzylamine hydrochloride.

The title compound can be prepared from intermediate 92,3-fluoro-2-(1,1-dioxo-1×6-[1,2]thiazinan-2-yl)benzonitrile according tothe procedure provided for intermediate 79. White solid, ¹H-NMR (500MHz, CD₃OD) δ ppm: 7.56–7.52 (1H, m), 7.40–7.34 (2H, m), 4.31 (2H, s),3.98–3.93 (1H, m), 3.68–3.64 (1H, m), 3.42–3.39 (2H, m), 2.42–2.37 (2H,m), 2.03–1.92 (2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₆N₂O₂FS: 259.09;found: 259.18.

3-Fluoro-2–1,2,4-triazol-1-yl-benzonitrile.

A mixture of 2,3-difluorobenzylnitrile (2.27 g, 16.3 mmol) and triazolesodium salt (1.33 g, 14.8 mmol) in tetrahydrofuran (5 mL) anddimethylformamide (10 mL) was stirred at 85° C. for 4 h. Afterconcentration, the residue was purified by flash chromatography (SiO₂)eluting with 25%–50% ethyl acetate/hexane. The isolated product wasrecrystallized from hot ethyl acetate/hexane to give the title compoundas white needles (1.51 g, 54% yield). ¹H-NMR (500 MHz, CDCl₃) δ ppm:8.50 (1H, d, J=2.4 Hz), 8.25 (1H, s), 7.69–7.67 (1H, m), 7.60–7.57 (2H,m). LCMS [M+H]⁺ calcd for C₉H₆N₄F: 189.16; found: 189.14.

(3-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine.

The title compound can be prepared from intermediate 94,3-fluoro-2–1,2,4-triazol-1-yl-benzonitrile. ¹H-NMR (500 MHz, CD₃OD) δppm: 9.61 (1H, d, J=2.9 Hz), 8.79 (1H, s), 7.82–7.74 (1H, m), 7.67–7.57(2H, m), 4.14–4.13 (2H, m). LCMS [M+H]⁺ calcd for C₉H₁₀N₄F: 193.08;found: 193.16.

5-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile.

A suspension of 2,5-diflurobenzonitrile (4.5 g, 32.35 mmol) and1,2,4-triazole sodium salt (3.6 g, 40 mmol) in dimethylformamide (40 mL)was heated at 80° C. for 15 h. The reaction mixture was then cooled,diluted with CH₂Cl₂ (200 mL), washed with water (3×30 mL) and brine (30mL), then dried (Na₂SO₄), filtered and concentrated to give a whitesolid which was purified by flash column chromatography (SiO₂) using 1:1to 3:1 ethyl acetate/Hexanes to afford the title compound (2.98 g, 49%yield) as a white powder. ¹H NMR (500 MHz, CDCl₃) δ: 8.70 (1H, s), 8.18(1H, s), 7.76 (1H, dd, J=9.0, 4.8 Hz), 7.55 (1H, dd, J=7.3, 2.8 Hz),7.51–7.47 (1H, m). LCMS (M+H) calcd for C₉H₆FN₄: 189.17; found: 189.10.

(5-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride.

A solution of intermediate 96,5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile (2.94 g, 15.59 mmol) inethanol (100 mL) and 1N HCl (50 mL) was degassed by bubbling N₂. Then,10% Pd/C was added, the flask evacuated and vented to H₂ three times andleft on a Parr shaker under a H₂ atmosphere (40 psi). After 6 h, thereaction mixture was filtered, concentrated and the aqueous solutionlyophilized to afford the title compound (4.07 g, 98%) as a whitepowder. LCMS (M+H) calcd for C₉H₁₀FN₄: 193.09; found: 193.15.

2-(1H-1,2,4-Triazol-1-yl)benzonitrile.

A suspension of 2-fluorobenzylnitrile (3.0 g, 25 mmol) and1,2,4-triazole sodium salt (2.4 g, 27 mmol) were stirred intetrahydrofuran (7 mL) and dimethylformamide (14 mL) at 95° C. for 18 h.After cooling and concentrating, the product was crystallized from hotCH₂Cl₂/hexane (1:1) to give the title compound as a white solid (4.25 g,100% yield). ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.74 (1H, s), 8.16 (1H, s),7.82 (1H, dd, J=4.9, 1.3 Hz), 7.77–7.25 (2H, m), 7.57–7.51 (1H, m). LCMS[M+H]⁺ calcd for C₉H₇N₄: 171.06; found: 171.12.

(2-(H-1,2,4-Triazol-1-yl)phenyl)methanamine hydrochloride.

Intermediate 98, 2-(1H-1,2,4-triazol-1-yl)benzonitrile (4.25 g, 25 mmol)was dissolved in ethanol (50 mL) and 1N HCl (25 mL). 10% Pd—C (1 g) wasadded and the mixture shaken under H₂ for 2 h at 50 psi. Afterfiltration through Celite and concentration, the residue was trituratedwith diethyl ether and the title compound was collected as a whitesolid. (3.94 g, 75% yield). ¹H-NMR (300 MHz, CD₃OD) δ ppm: 9.01 (1H, s),8.32 (1H, s), 7.78–7.64 (4H, m), 4.15 (2H, s). LCMS [M+H]⁺ calcd forC₉H₁₁N₄: 175.09; found: 175.17.

2-(1,1-Dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzonitrile.

Added to a solution of 1,1-dioxo[1,2]thiazinane (3.37 g, 25 mmol) indimethylformamide (35 mL) was sodium hydride (0.675 g, 25 mmol, 95%) andthe mixture stirred at room temperature for 15 min. 2-Fluorobenzonitrile(3.37 mL, 31.3 mmol) was added and the mixture stirred at 80° C. for 18h. The mixture was cooled, diluted with water and extracted with ethylacetate. The organic phase was washed with water and brine, then dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography (SiO₂) eluting with 10%-100% ethyl acetate/hexane. Theisolated solid was recrystallized from hot ethyl acetate/hexane (2:1) togive the title compound as white crystals (4.15 g, 70% yield). ¹H-NMR(300 MHz, CDCl₃) δ ppm: 7.70 (1H, dd, J=7.7, 1.1 Hz), 7.64–7.53 (2H, m),7.41 (1H, td, J=7.3, 1.6 Hz), 3.72 (2H, t, J=5.5 Hz), 3.32 (2H, t, J=6.0Hz), 2.40–2.32 (2H, m), 2.05–1.97 (2H, m). LCMS [M+H]⁺ calcd forC₁₁H₁₂N₂O₂S: 237.06; found: 237.10.

2-(1,1-Dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzylamine hydrochloride.

Intermediate 100, 2-(1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl)benzonitrile,(2.63 g, 11.14 mmol) was dissolved in ethanol (150 mL) and 1N HCl (13mL). Added to this was 10% Pd—C (0.5 g) and the mixture shaken under H₂at 55 psi for 24 h. Filtration through Celite followed by concentrationgave the title compound as a white solid (2.93 g, 95% yield). ¹H-NMR(300 MHz, CD₃OD) δ ppm: 7.61–7.47 (4H, m), 4.30 (2H, q, J=13.7 Hz),3.96–3.87 (1H, m), 3.49–3.36 (3H, m), 2.40–2.31 (2H, m), 2.05–1.96 (2H,m). LCMS [M+H]⁺ calcd for C₁₁H₁₇N₂SO₂: 241.10; found: 241.10.

(3,5-Difluoropyridin-2-yl)methanamine hydrochloride.

A mixture of 3,5-difluoropicolinonitrile (1.4 g, 10 mmol), conc. HCl (12ml) and 10% Pd—C (200 mg) in 1:1 ethanol/tetrahydrofuran was shakenunder a hydrogen atmosphere (50 psi) for 5 h. The reaction mixture wasfiltered and the ethanol removed in vacuo. The remaining solution waslyophilized to afford an off-white solid (2.16 g, 100% yield). LCMS(M+H) calcd for C₆H₇F₂N₂: 145.06; found: 145.12.

(5-Chloropyridin-2-yl)methanamine.

A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3mL) and 10% Pd—C (1.0 g) in ethanol (100 mL) was shaken under a hydrogenatmosphere (40 psi) for 2 h. The reaction mixture was filtered,concentrated and the resulting residue taken up in satd NaHCO₃ (50 mL)and extracted with CH₂Cl₂ (4×25 mL). The combined CH₂Cl₂ layers weredried (Na₂SO₄), filtered and concentrated to give the title compound asa yellow oil (2.0 g, 51% yield). LCMS (M+H) calcd for C₆H₈ClN₂: 143.04;found: 143.07. ¹HNMR (500 MHz, CDCl₃) δ ppm: 8.56–8.51 (1H, br d),7.66–7.60 (1H, m), 7.28–7.14 (1H, m) 3.97 (2H, s), 1.72 (2H, s).

2-(Bromomethyl)-5-fluorobenzonitrile.

N₂ was passed through a mixture of 5-fluoro-2-methylbenzonitrile (28.51g, 211 mmol), NBS (41.31 g, 232 mmol) and AIBN (2.5 g, 15 mmol) in CCl₄(845 mL) for 10 min after which the reaction was heated at reflux for 8h. After standing at room temperature overnight, the reaction mixturewas filtered and the filter cake washed with CCl₄ (500 mL). The combinedfiltrate was evaporated to give a yellow oil. Flash chromatography(SiO₂) using 5–25% ethyl acetate/Hexanes as eluent afforded the titlecompound (29.74 g, 66% yield) as a pale yellow oil. ¹H NMR (500 MHz,CDCl₃) δ: 7.55 (1H, dd, J=8.6, 5.2 Hz), 7.37 (1H, dd, J=7.9, 2.8 Hz),7.32–7.28 (1H, m), 4.61 (2H, s).

2-((1,3-Dioxoisoindolin-2-yl)methyl)-5-fluorobenzonitrile.

To a stirred solution of intermediate 104,2-(bromomethyl)-5-fluorobenzonitrile (29.72 g, 139 mmol) and phthalimide(32.69 g, 222 mmol) in dimethylformamide (300 mL) was added Cs₂CO₃(67.87 g, 208 mmol). After stirring vigorously for 1 h, the reactionmixture was poured into water (1.2 L). The precipitated product wasfiltered, washed with water (600 mL) and methanol (150 mL) to give awhite solid. The solid was taken up into 1 L of water/methanol (2:1) towhich was added K₂CO₃ (12 g) and the mixture stirred at 40° C. After 30min., the mixture was cooled and filtered. The filter cake was washedwith water (500 mL), and dried under vacuum to afford the title compound(38.91 g, 94% yield) as a white powder. ¹H NMR (500 MHz, CDCl₃) δ: 7.89(2H, dd, J=5.5, 3.1 HZ), 7.76 (5.5, 3.1 Hz), 7.41 (1H, dd, J=8.6, 5.2Hz), 7.38 (1H, dd, J=7.9, 2.8 Hz), 7.24 (1H, td, J 8.2, 2.8 Hz), 5.06(2H, s). LCMS (M+H) calcd for C₁₆H₁₀FN₂O₂: 281.07; found: 281.15.

tert-Butyl 2-cyano-4-fluorobenzylcarbamate.

A suspension of intermediate 105,2-((1,3-dioxoisoindolin-2-yl)methyl)-5-fluorobenzonitrile, (5.6 g, 20mmol) in dimethylformamide (20 mL) was warmed until it was dissolved. Tothis was added tetrahydrofaran (100 mL) and the mixture placed in apre-heated (70° C.) oil bath. Hydrazine monohydrate was added to thisand the reaction stirred for 8 h. The resulting white slurry was left atambient temperature overnight. To this slurry was addeddi-tert-butyldicarbonate (6.55 g, 30 mmol) and the mixture stirred for 6h at room temperature. The reaction mixture was diluted with ether (100mL), filtered and the filtrate treated with activated carbon at 40° C.After filtration and concentration the crude product was purified byflash chromatography, using 20–30% ethyl acetate/Hexanes as eluent, toprovide the title compound (2.88 g, 58% yield) as a light yellow powder.¹H NMR (500 MHz, CDCl₃) δ: 9.46 (1H, br s), 7.61 (1H, dd, J=7.9, 2.1Hz), 7.34 (1H, dd, J=8.2, 4.6 Hz), 7.22 (1H, td, J=8.6, 2.4 Hz), 4.71(2H, s), 1.59 (9H, s). LCMS (M+H) calcd for C₁₃H₁₆FN₂O₂: 251.12; found:251.22.

2-(Aminomethyl)-5-fluorobenzonitrile trifluoroacetic acid salt.

A round-bottom flask was charged with intermediate 106, tert-butyl2-cyano-4-fluorobenzylcarbamate, (1.9 g, 7.591 mmol) then treated withtrifluoroacetic acid (20 ml) at room temperature. After 1 h, thereaction mixture was concentrated to give a yellow oil which wasdissolved in CHCl₃ and re-concentrated to afford the title compound(2.01 g, 100% yield) as a pale yellow solid. LCMS (M+H) calcd forC₈H₈FN₂: 151.07; found: 151.08.

(2,5-Dibromo-4-fluorophenyl)methanamine.

A solution of 2,5-dibromo-4-fluorobenzyl bromide (0.350 g, 1 mmol) in 7MNH₃/MeOH was heated in a sealed tube at 100° C. for 2 h. The reactionmixture was cooled and concentrated to give a white solid which wasdissolved in CH₂Cl₂ and treated with Et₃N (1 mL) then concentrated. Theresulting residue was triturated with ethyl acetate (25 mL), filteredand concentrated to give the title compound (0.291 g) as a pale yellowoil. HRMS (M+H) calcd for C₇H₇Br₂FN: 283.94; found: 283.93.

4-Fluoro-2-methylsulfanyl-benzylamine.

Under N₂, 4-fluoro-2-(methylthio)benzonitrile (1.67 g, 0.1 mol) wasdissolved in 20 mL tetrahydrofuran and treated with 10 mL 2M BH₃.Me₂S.This was heated at 60° C. for 2 hrs. Heating was discontinued and 5 mLMeOH was cautiously added, followed by the cautious addition of 4 mL 6NHCl. Additional H₂O (20 mL) was added followed by ethyl acetate. Thelayers were separated. The aqueous layer was made basic with 1N NaOH andextracted with CH₂Cl₂. The extracts were dried (MgSO₄), filtered,concentrated and dried in vacuo to give 1.3 g of the title compound as asolid (Yield 76%). ¹H NMR (500 MHz, CDCl₃) δ ppm: 7.20–7.31 (1H, m) 6.90(1H, dd, J=2.4 Hz) 6.75–6.86 (1H, m) 3.86 (2H, s) 2.47 (3H, s); LC/MSm/z 172.

2-(Aminomethyl)-5-fluorobenzenamine hydrochloride.

2-Amino-4-fluorobenzonitrile (Fritz Hunziker et al. Eur. J. Med. Chem.1981, 16, 391) (0.300 g, 1.68 mmol), was dissolved in acetic anhydride(5 mL) and the solution was stirred at 23° C. for 18 h. An additionalportion of acetic anhydride (3 mL) was added to dissolve theN-(2-cyano-5-fluorophenyl)acetamide. Then palladium (10% on charcoal)(25 mg) was added and the mixture was agitated under H₂ (34 psi) for 72h. The Pd—C was removed by filtration on Celite and the filtrateconcentrated in vacuo to afford a bis-acetamide: LCMS (M+H)⁺ m/z 225.This was heated at reflux with HCl (6N, 10 mL) for 30 min. The acid wasremoved under reduced pressure to give a solid which was crystallizedfrom MeOH-ether to afford the title compound (0.120 g, 51% yield). ¹HNMR (400 MHz, MeOD) δ ppm: 7.51 (1H, m), 6.96 (2H, m), 4.20 (2H, s).

4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzonitrile.

A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g,5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs₂CO₃ (2.28 g, 7.0mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos)(0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15min. Pd₂ dba₃ was introduced and the reaction mixture heated at 105° C.for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane,and then filtered through Celite. The resulting mixture was concentratedin vacuo and subjected to column chromatography on silica gel withhexanes:ethyl acetate (3:7) gradient as the eluent to afford the titlecompound as a white solid (0.887 g, 87% yield): ¹H NMR (400 MHz, CDCl₃)δ ppm: 7.69 (1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07(1H, ddd, J 2.5, 7.6, 8.6 Hz), 3.96 (2H, t, J=7.0 Hz), 2.62 (2H, t,J=8.1 Hz), 2.30–2.22 (2H, m); LCMS (⁺ESI, M+H⁺) m/z 205.

4-Fluoro-2-(2-oxopiperidin-1-yl)benzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 111 ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.71 (1H, dd, J=5.7,8.7 Hz), 7.14–7.06 (1H, m), 7.08 (1H, dd, J=2.4, 9.0 Hz), 3.65 (2H, t,J=5.7 Hz), 2.60 (2H, t, J=6.3 Hz), 2.05–1.95 (4H, m); LCMS (⁺ESI, M+H⁺)m/z 219.

4-Fluoro-2-(2-oxoazepan-1-yl)benzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.68 (1H, dd,J=5.8, 8.6 Hz), 7.08 (1H, ddd, J=2.5, 7.6, 8.6 Hz), 7.01 (1H, dd, J=2.5,9.0 Hz), 3.77–3.76 (2H, m), 2.75–2.72 (2H, m), 1.91–1.86 (6H, m); LCMS(⁺ESI, M+H⁺) m/z 233.

N-(2-Cyano-5-fluorophenyl)-N-methylacetamide.

The title compound can be prepared according to the procedure providedfor intermediate 111 ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.79–7.75 (1H, m),7.32–7.19 (1H, m), 7.10–7.07 (1H, m), 3.42 (0.6H, brs), 3.30 (2.4H, s),2.32 (0.6H, brs), 1.91 (2.4H, s); LCMS (⁺ESI, M+H⁺) m/z 193; HPLC: 94%(220 nm).

2-(2-Oxoazetidin-1-yl)benzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.02 (1H, d,J=8.4 Hz), 7.76 (1H, dd, J=1.5, 7.8 Hz), 7.69–7.65 (1H, m), 7.23 (1H,s), 4.04 (2H, t, J=4.8 Hz), 3.16 (2H, t, J=4.8 Hz). LCMS (⁺ESI, M+H⁺)m/z 173.

2-(2-Oxooxazolidin-3-yl)benzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.71 (1H, dd,J=1.5, 7.6 Hz), 7.68–7.63 (1H, m), 7.58 (1H, d, J=7.6 Hz), 7.38 (1H, dt,J=1.3, 7.6 Hz), 4.57 (2H, t, J=7.8 Hz), 4.21 (2H, t, J=7.8 Hz); LCMS(⁺ESI, M+H⁺) m/z 189.

4-Fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile.

A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g,5.00 mmol), 2-oxazolidone (0.390 g, 4.50 mmol), K₂CO₃ (0.970 g, 7.0mmol) and xantphos (0.231 g, 0.40 mmol) in dioxane (10 mL) was degassedwith argon for 15 min. Pd₂ dba₃ (0.140 g, 0.15 mmol) was introduced andthen the reaction mixture was heated at 70° C. for 18 h. The mixture wascooled, diluted with dioxane, and then filtered through Celite. Theresulting mixture was concentrated in vacuo and subjected to columnchromatography on silica gel with hexanes:ethyl acetate (1:1) to (3:7)gradient as the eluent to afford the title compound as a white solid(0.460 g, 50% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.73 (1H, dd,J=5.8, 8.6 Hz), 7.43 (1H, dd, J=2.5, 9.6 Hz), 7.11 (1H, ddd, J=2.5, 7.5,8.7 Hz), 4.60 (2H, t, J=7.1 Hz), 4.29 (2H, t, J=7.1 HJz); LCMS (⁺ESI,M+H⁺) m/z 207.

3-(2-(Aminomethyl)-5-fluorophenyl)oxazolidin-2-one hydrochloride.

¹H NMR (400 MHz, MeOD) δ ppm: 7.73 (1H, dd, J=6.0, 8.6 Hz), 7.43 (1H,dd, J=2.5, 9.5 Hz), 7.11 (1H, ddd, J=2.5, 7.5, 8.6 Hz), 4.64 (2H, t,J=7.7 Hz), 4.17 (2H, t, J=7.7 Hz), 4.14 (2H, s); LCMS (⁺ESI, M+H⁺) m/z211.

4-Fluoro-2-(2-oxoazetidin-1-yl)benzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 117 ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.06 (1H, dd,J=10.7, 2.6 Hz), 7.58 (1H, dd, J=8.6, 6.3 Hz), 7.87 (1H, td, J=8.6, 2.5Hz), 4.25 (2H, t, J=5.0 Hz), 3.26 (2H, t, J=5.0 Hz); LCMS (⁺ESI, M+H⁺)m/z 191.

1-(2-(Aminomethyl)-5-fluorophenyl)azetidin-2-one hydrochloride.

¹H NMR (400 MHz, DMSO/D₂O) δ ppm: 7.54 (1H, dd, (t), J=8.6 Hz), 7.25(1H, dd, J=10.8, 2.5 Hz), 7.17 (1H, td, J=8.6, 2.5 Hz), 4.12 (2H, s),3.79 (2H, t, J=4.6 Hz), 3.09 (2H, t, J=4.6 Hz); LCMS (⁺ESI, M+H⁺) m/z195.

(R)-2-(2-((tert-Butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.68 (1H, dd,J=5.8, 8.8 Hz), 7.19 (1H, dd, J=2.5, 9.1 Hz), 7.11–7.07 (1H, m),4.46–4.42 (1H, m) 3.55 (2H, d, J=3.3 Hz), 2.72–2.52 (2H, m), 2.43–2.33(1H, m), 2.09–2.01 (1H, m), 0.81 (9H, s), −0.04 (3H, s), −0.07 (3H, s);LCMS (⁺ESI, M+H⁺) m/z 349.

(S)-2-(2-((tert-Butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.68 (1H, dd,J=5.8, 8.6 Hz), 7.19 (1H, dd, J=2.5, 9.4 Hz), 7.11–7.07 (1H, m),4.46–4.43 (1H, m) 3.55 (2H, d, J=3.3 Hz), 2.72–2.52 (2H, m), 2.43–2.33(1H, m), 2.09–2.01 (1H, m), 0.81 (9H, s), −0.04 (3H, s), −0.07 (3H, s);LCMS (⁺ESI, M+H⁺) m/z 349.

4-Fluoro-2-(thiazol-2-ylamino)benzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.21 (1H, s),8.39–8.35 (1H, m), 7.97 (1H, d, J=5.0 Hz), 7.23–7.13 (3H, m); LCMS(⁺ESI, M+H⁺) m/z 220.

4-Fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzonitrile.

The title compound can be prepared according to the procedure providedfor intermediate 111. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.30 (1H, dd,J=6.5, 8.8 Hz), 7.96 (1H, s), 7.26–7.19 (2H, m), 2.64 (3H, s); LCMS(⁺ESI, M+H⁺) m/z 235.

1-(2-(Aminomethyl)-5-fluorophenyl)piperidin-2-one hydrochloride salt.

To a stirred solution of intermediate 112,4-fluoro-2-(2-oxopiperidin-1-yl)benzonitrile (150 mg, 0.69 mmol) in H₂O(10 mL) was added ethanol (10 mL) 10% palladium on charcoal (50 mg) and1N HCl (2.1 mL, 20.6 mmol). The reaction was shaken in a Parr systemunder H₂ (40 psi) for 1 h. Then the Pd/C catalyst was removed byfiltration on Celite and the filtrate was concentrated in vacuo to yielda solid. Toluene (2×50 mL) was added to the solid and the solution wasevaporated in vacuo. LCMS (M+H)⁺ m/z 170.

1-Bromo-4-fluoro-2-methoxybenzene.

To a mixture of 2-bromo-5-fluorophenol (10 g, 50.8 mmol) and iodomethane(11.2 g, 78.7 mmol) in dimethylformamide (100 mL) was added potassiumcarbonate (10.9 g, 79 mmol) and the mixture stirred at room temperaturefor 3 hrs. The mixture was diluted with water (100 mL) and extractedwith ether (50 mL×3). The combined extracts were washed with brine,dried over anhydrous magnesium sulfate, and concentrated in vacuo toobtain 11.3 g of 1-bromo-4-fluoro-2-methoxybenzene as an amber coloredoil.

4-Fluoro-2-methoxybenzonitrile.

To a solution of intermediate 126, 1-bromo-4-fluoro-2-methoxybenzene(9.0 g) in N-methylpyrrolidone (100 mL, Sure Seal; Aldrich) was addedCuCN (6.6 g, 73.7 mmol, 1.8 eq.; Aldrich), and the mixture stirred at180° C. under anhydrous nitrogen for 5.5 hrs. After cooling, 14% aqueousNH₄OH (330 mL) was added and stirring continued for 45 min at roomtemperature. The mixture was extracted with ether (100 mL×3), and thecombined extracts washed sequentially with dilute aqueous NH₄OH, diluteHCl and brine, then dried (MgSO₄), and concentrated to provide the titlecompound (5.2 g, Yield 85% in 2 steps) as a white solid: ¹H NMR (CDCl₃,500 MHz) δ ppm: 3.91 (3H, s, OMe), 6.69 (1H, dd, J=2.3 Hz, J=10.5 Hz,Ar—H), 6.72 (1H, dt, J=2.5 Hz, J=J=8.0 Hz, Ar—H), 7.55 (1H, dd, J=6.5Hz, J=8.5 Hz, Ar—H); ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm: 56.49, 98.16,100.06, 100.27, 108.31, 108.50, 115.83 135.37, 135.46, 163.25, 163.34165.47, 167.50. An analytical sample was obtained by trituration withether: Anal. calcd for C₈H₆FNO: C, 63.57; H, 4.00; N, 9.26; found: C,63.36; H, 3.91; N, 9.16.

4-Fluoro-2-methoxybenzylamine hydrochloride.

To a mixture of intermediate 127, 4-fluoro-2-methoxybenzonitrile, (800mg, 5.3 mmol) and conc.HCl (0.53 mL, 6.36 mmol, 1.2 eq.) in ethanol (20mL) was added 10% Pd—C (100 mg; Aldrich), and the mixture hydrogenatedat 1 atm hydrogen for 15 hrs at room temperature. To this mixture wasadded an additional amount of conc.HCl (1 mL) and 10% Pd—C (200 mg) andthe reaction allowed to continue for another 40 hrs. The mixture wasfiltered through Celite and the filtrate concentrated in vacuo todryness. The residue was triturated with ether to provide the titlecompound (895 mg, Yield 88%) as a white powder: ¹H NMR (CDCl₃, 500 MHz)δ ppm: 3.84 (3H, s, OMe), 3.91 (2H, d, J=5.5 Hz, N—CH₂), 6.81 (1H, dt,J=2.5 Hz, J=J=8.5 Hz, Ar—H), 6.99 (1H, dd, J=2.5 Hz, J=11.3 Hz, Ar—H),7.47 (1H, dd, J=7 Hz, J=8.5 Hz, Ar—H); ³C NMR (CDCl₃, 125.8 Hz) δ ppm:36.76, 56.03, 99.30, 99.51 106.28, 106.45, 117.93, 117.95, 131.60,131.69, 158.56, 158.64, 162.28, 164.22. HRMS (ESI) calcd for C₈H₁₁FNO(M+H) 156.0825, found 156.0830.

4-Fluoro-2-hydroxybenzonitrile.

A mixture of intermediate 127, 4-fluoro-2-methoxybenzonitrile, (4.53 g,30 mmol;) and AlCl₃ (5.0 g, 37.6 mmol; Aldrich) in anhydrous toluene (30mL) was stirred at approximately 130° C. for 18 hrs. After cooling, icewater (˜50 mL) was added and the resulting mixture extracted with ether(20 mL×2). The combined extracts were washed sequentially with water andbrine, then dried (MgSO₄), and concentrated in vacuo to provide thetitle compound (3.90 g, 28.5 mmol, Yield 95%) as a white solid: ¹H NMR(DMSO-d₆, 300 MHz) δ ppm: 6.74–6.84 (2H, m, Ar—Hs), 7.71 (1H, dd, J=7Hz, J=8.5 Hz, Ar—H), 11.64 (1H, s, OH); ¹³C NMR (DMSO-d₆, 75.5 Hz) δppm: 95.13 102.45, 102.78, 106.53, 106.83 115.53, 134.68, 134.84,161.41, 161.58, 163.00, 166.35. HRMS (ESI−) calcd for C₇H₃NOF (M−H)136.0199, found 136.0199.

4-Fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile.

To a solution of intermediate 129, 4-fluoro-2-hydroxybenzonitrile, (685mg, 5 mmol) in dimethylformamide (8 mL, Sure Seal; Aldrich) was addedNaH (200 mg, 5 mmol; 60% oil dispersion; Aldrich), and the mixturestirred for 5 min under an anhydrous nitrogen atmosphere. To this wasadded 4-(2-chloroacetyl)morpholine (900 mg, 5.5 mmol, 1.1 eq.; AvocadoOrganics), and stirring continued at room temperature for 21 hrs. Thereaction was quenched by careful addition of water (30 mL). Theresulting mixture was extracted with CH₂Cl₂ (25 mL×2). The combinedextracts were washed with brine, dried (MgSO₄) and concentrated. Theresidue was triturated to obtain 1.10 g (4.17 mmol, Yield 83%) of thetitle compound as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ ppm: 3.63(2H, t, J=4 Hz, NCH₂), 3.67 (1H, m, OCH), 3.72 (1H, m, OCH), 4.86 (2H,s, OCH₂), 6.80–6.86 (2H, m, Ar—Hs), 7.61 (1H, dd, J=8.5 Hz, 6.1 Hz,Ar—H); ¹³C NMR (CDCl₃, 125.77 Hz) δ ppm: 42.63, 46.04, 66.80, 68.33,98.45, 98.47, 101.57, 101.79, 109.56, 109.74, 115.42, 135.48, 135.57,161.26, 161.35, 114.79, 165.23, 167.28. HRMS calcd for C₁₃H₁₄N₂O₃F (M+H)265.0988, found 265.0998.

2-(2-(Aminomethyl)-5-fluorophenoxy)-1-morpholinoethanone hydrochloride.

A solution of intermediate 130,4-fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile, (500 mg, 1.89 mmol)in warm ethanol (30 mL) and ethyl acetate (30 mL) was mixed withconc.HCl (0.32 mL, 3.78 mmol, 2 eq.). To this was added 10% Pd—C (100mg; Aldrich), and the mixture was hydrogenated at 1 atm of hydrogen for20 hrs at room temperature. To this mixture was added an additionalamount of 10% Pd—C (50 mg) and stirring continued for another 7 hrs. Themixture was filtered through Celite and the filtrate concentrated invacuo to dryness. The residue was triturated with ethyl acetate, thenwith ethanol to obtain the title compound (168 mg, Yield 29%) as anoff-white powder: ¹H NMR (CD₃OD, 500 MHz) δ ppm: 3.55 (2H, t, J=5 Hz,NCH₂), 3.62 (2H, t, J=5 Hz, NCH₂), 3.70 (2H, t, J=5 Hz, OCH₂), 3.75 (2H,t, J=5 Hz, OCH₂), 4.17 (2H, s, NCH₂), 5.17 (2H, s, OCH₂), 6.82 (1H, dt,J=2.5, 8.5 Hz, Ar—H), 7.05 (1H, dd, J=2.5, 10.5 Hz, Ar—H), 7.43 (1H, dd,J=6.5, 8.5 Hz, Ar—H); ¹³C NMR (CD₃OD, 125.77 Hz) δ ppm: 39.40, 42.49,44.97, 66.11, 66.46, 66.59, 101.38, 101.59, 108.40, 108.57, 118.40,132.53, 132.62, 158.43, 158.52, 63.87, 165.83, 168.27. HRMS (ESI) calcdfor C₁₃H₁₈N₂O₃F (M+H) 269.1301, found 269.1301.

Dimethyl-carbamic acid 2-cyano-5-fluoro-phenyl ester.

Under N₂, a stirred solution of intermediate 129,4-fluoro-2-hydroxybenzonitrile (685 mg, 5.00 mmol), dimethylcarbamoylchloride, and triethylamine (606 mg, 6 mmol) in dichloroethane (10 mL)was heated at reflux for 20 hrs. The cooled mixture was diluted withdichloroethane (10 mL) washed with water, and brine. The organic layerwas separated, dried (Na₂SO₄), concentrated, and the residue purified bycolumn chromatography (SiO₂, 5% ethyl acetate-CH₂Cl₂) to provide 700 mg(Yield 67%) of the title compound as a white crystalline solid: ¹H NMR(CDCl₃, 500 MHz) δ ppm: 3.03 (3H, s, NMe), 3.15 (3H, s, NMe), 6.99 (1H,dt, J=2.5 Hz, 8.5 Hz, Ar—H), 7.23 (1H, dd, J=2.5 Hz, 9.5 Hz, Ar—H), 7.61(1H, dd, J=9 Hz, 6 Hz, Ar—H); ¹³C NMR (CDCl₃, 125.77 Hz) δ ppm: 36.76,37.06, 102.84, 102.86, 111.59, 111.79, 113.24, 113.42, 114.99, 134.36,134.45, 152.54, 155.06, 155.16, 164.26, 166.31. HRMS (ESI) calcd forC₁₀H₁₀N₂O₂F (M+H) 209.0726, found 209.0722.

Dimethyl-carbamic acid 2-aminomethyl-5-fluoro-phenyl esterhydrochloride.

To a solution of intermediate 132, dimethyl-carbamic acid2-cyano-5-fluoro-phenyl ester, (340 mg, 1.63 mmol) in ethyl acetate (20mL) and ethanol (20 mL), was added conc.HCl (0.4 mL) and 10% Pd—C (100mg) and the mixture hydrogenated in a Parr Shaker at 55 psi of hydrogenfor 20 hrs. The reaction mixture was filtered through Celite, and thefiltrate concentrated in vacuo to give an oil which was partitionedbetween ethyl acetate (10 mL) and water (10 mL). After separation, theaqueous phase was washed with additional ethyl acetate (5 mL). Thecombined extracts were concentrated in vacuo to dryness. The residualoil was triturated with ether to provide 145 mg (Yield 38%) of the titlecompound, as a tan powder: ¹H NMR (CD₃OD, 500 MHz) δ ppm: 3.06 (3H, s,NMe), 3.21 (3H, s, NMe), 4.11 (2H, s, NCH₂), 7.13 (2H, m, Ar—Hs), 7.60(1H, m, Ar—H); ¹³C NMR (CD₃OD, 125.77 Hz) δ ppm: 36.03, 36.25 37.58,110.79, 110.99, 113.26, 113.43, 122.32, 132.18, 132.25, 151.55, 154.72,162.69, 164.67. HRMS (ESI) calcd for C₁₀H₁₃N₂O₂F (M+H) 213.1039, found213.1039.

2-(Benzyloxy)-4-fluorobenzonitrile.

Benzyl alcohol (13 mL, 125 mmol) was slowly added to a stirredsuspension of NaH (95%, 2.86 g, 113 mmol) in toluene (200 mL) at roomtemperature. After 30 min, 2,4-difluorobenzonitrile (15.3 g, 110 mmol;Aldrich) was added all at once and stirring continued overnight (18 h).After this, the reaction mixture was washed with water (2×25 mL) andbrine (25 ml). The organic layer was dried (Na₂SO₄), filtered andconcentrated to give a white slurry which was triturated with hexanesand filtered to afford the title compound as a white solid (20.34 g, 81%yield). ¹H NMR (500 MHz, CDCl₃): 7.59–7.55 (1H, m), 7.45–7.34 (5H, m),6.75–6.71 (2H, m), 5.19 (2H, s); ¹³C NMR (125.76 MHz, DMSO-d₆) δ ppm:71.16, 98.75, 101.54, 101.75, 108.66, 108.84, 115.83, 127.16, 128.58,128.94, 135.03, 135.44, 135.54, 162.22, 162.31, 165.26, 167.29. LCMScalcd for C₁₄H₁₁FNO: 228.2; found: 228.0.

2-Hydroxy-4-fluoro-benzylamine hydrochloride.

A solution of intermediate 134, 2-(benzyloxy)-4-fluorobenzonitrile,(9.03 g, 39.7 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) wasstirred with 10% palladium on carbon (1.67 g,) and concentratedhydrochloric acid (12 mL, 144 mmol) under a hydrogen atmosphere (60 psi)for four days. The catalyst was removed by filtration through Celite,and the filtrate was concentrated. The crude product was triturated withether and the resulting solid collected by filtration to give the titlecompound (5.24 g, 74% yield) as a pale orange solid. ¹H NMR (500 MHz,DMSO-D6) δ ppm: 10.81 (1H, s), 8.18 (3H, s), 7.36 (1H, t, J=7.3 Hz),6.79 (1H, dd, J=10.8, 2.6 Hz), 6.66 (1H, dt, J=8.5, 2.3 Hz), 3.90 (2H,d, J=5.2 Hz).

(2,2-Diethoxyethyl)(o-tolyl)sulfane.

In ethanol (50 mL) was dissolved sodium metal (1.6 g, 66 mmol) at 23° C.2-Methylbenzenethiol (8.1 mL, 68 mmol) was slowly added to thissolution, followed by bromoacetaldehyde diethylacetal (9.50 mL, 63mmol). The reaction mixture was stirred at reflux for 18 h. The solventwas then evaporated in vacuo and the residue was washed with H₂O (100mL) and extracted with ether (100 mL). The organic solution was dried(MgSO₄), concentrated in vacuo and purified by distillation to affordthe title compound (13.48 g, 82% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm:7.33 (1H, d, J=7.9 Hz), 7.16–7.08 (3H, m), 4.65 (1H, t, J=5.6 Hz), 3.66(2H, q, J=7.0 Hz), 3.55 (2H, q, J=7.0 Hz), 3.09 (2H, d, J=5.6 Hz), 2.38(3H, s), 1.20 (6H, t, J=7.0 Hz). LCMS (M+H)⁺ m/z 241 (t=2.65 min.).

7-Methylbenzo[b]thiophene.

To a solution of intermediate 136, (2,2-diethoxyethyl)(o-tolyl)sulfane(0.58 g, 2.41 mmol) in chlorobenzene (20 mL) was added polyphosphoricacid. The reaction mixture was stirred at reflux for 18 h. Water (100mL) was then added and the organic material was extracted with CH₂Cl₂(2×50 mL). The organic solution was dried (MgSO₄) and concentrated invacuo to afford 335 mg (94% yield) of the title compound: ¹H NMR (400MHz, CDCl₃) δ: 7.68 (1H, d, J=7.8 Hz), 7.43 (1H, d, J=5.4 Hz), 7.36 (1H,d, J=5.4 Hz), 7.30 (1H, dd, J=7.8, 7.1 Hz), 7.14 (1H, d, J=7.1 Hz), 2.58(3H, s); LCMS (M+H)⁺ m/z 148.

7-(Bromomethyl)benzo[b]thiophene.

To a solution of intermediate 137, 7-methylbenzo[b]thiophene (1.0 g, 6.5mmol) in CCl₄ (20 mL) was added benzoyl peroxide (1.1 g, 4.54 mmol)followed by portionwise addition of NBS (1.15 g, 6.5 mmol). The reactionmixture stirred at reflux while irradiating with a 250 W lamp. Thereaction mixture was stirred at reflux for 3 h. The solution was cooled,filtered and the solvent evaporated in vacuo. The residue was subjectedto column chromatography on silica gel with hexanes as the eluent toafford the title compound (0.570 g, 33% yield): ¹H NMR (400 MHz, CDCl₃)δ: 7.80 (1H, dd, J=7.8, 1.7 Hz), 7.49 (1H, d, J=5.4 Hz), 7.40–7.33 (3H,m), 4.78 (2H, s). LCMS (M+H)⁺ m/z 209.

Benzo[b]thiophen-7-ylmethanamine hydrochloride.

To intermediate 138, 7-(bromomethyl)benzo[b]thiophene (0.20 g, 0.96mmol) was added a methanolic solution saturated with ammonia (30 mL).The reaction mixture was heated in a steal bomb at 70° C. for 18 h. Thesolvent was evaporated in vacuo and the residue was dissolved in MeOH(10 mL). HCl (1M in ethanol, 1 mL) was added to the solution and thesolvents were removed in vacuo to afford the title compound (0.177 g,99% yield); LCMS (M+H)⁺ m/z 164.

Intermediates 140–148

The synthesis of intermediates 140–148 provides representativeprocedures for the synthesis of other compounds in the invention.

N-{4-Fluoro-2-(methylcarbamoyl)benzyl}-3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.

A mixture of intermediate 27,3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid (0.172 g, 0.54 mmol) and intermediate 39,2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.177g, 0.60 mmol) in dichloromethane (10 ml) was treated at 22° C. withtriethylamine (0.17 ml, 1.22 mmol) followed bybenzotriazole-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP) (0.340 g, 0.65 mmol). After 3 h, the reaction mixture wasdiluted with ethyl acetate, washed with saturated sodium bicarbonate andbrine then dried over anhydrous magnesium sulfate. Evaporation of thesolvent followed by chromatography of the residue on silica gel (elutiongradient ethyl acetate 50–100% in toluene) gave 0.260 g (100% yield) ofthe title amide as a white solid. ¹HNMR 400 MHz (CDCl₃) 5 (Ppm): 1.70(3H, d, J=6.6 Hz, CH₃), 3.01 (3H, d, J=4.7 Hz, NCH₃), 3.89 (2H, m, CH₂),4.14 (1H, m, CH), 4.29 (1H, m, CH), 4.53 (2H, d, J=6.7 Hz, NCH₂), 4.69(1H, q, J=6.6 Hz, OCH), 5.35 (2H, s, OCH₂), 6.69 (1H, broad q, NH), 7.09(1H, m, aromatic), 7.16 (1H, m, aromatic), 7.32 (3H, m, aromatics), 7.42(1H, m, aromatic), 7.47 (2H, m, aromatics), 8.61 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₅H₂₆FN₄O₅ [M+H⁺]: 481.1887: found: 481.1884.

N-(4-fluorobenzyl)-3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.

A solution of intermediate 22 (82 mg, 0.22 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (152 mg, 0.4 mmol) in 1 mL dimethylformamidewas stirred for 20 min under N₂. 4-Fluorobenzylamine (38 mg, 0.3 mmol)was then added and stirring continued for 16 hrs. The dimethylformamidewas evaporated under reduced pressure and the remaining residuedissolved in CH₂Cl₂. The resulting solution was washed with dil HCl. Thesolvent was removed under reduced pressure and the crude productpurified by chromatography (SiO₂, ethyl acetate) to provide the titlecompound (70 mg, Yield=66%). LC/MS m/e 484 (M+H).

3-(Benzyloxy)-2-(6-fluoro-1-oxoisoindoline-2-carbonyl)-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one.

To a stirred suspension of intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid, (1.65 g, 5 mmol) in CH₂Cl₂ (15 mL) was added a catalytic amount ofdimethylformamide and 10 mL of a 2 M oxalylchloride in CH₂Cl₂. After 30min., the resulting clear yellow solution was concentrated to afford alight brown solid. This solid was dissolved in CH₂Cl₂ (50 mL) and addedto a stirred mixture of intermediate 107,2-(aminomethyl)-5-fluorobenzonitrile trifluoroacetic acid salt, (1.77 g,5.97 mmol) and diethylisopropylamine (2.6 mL, 15 mmol) in CH₂Cl₂ (100mL). After 1 h, the clear brown reaction mixture was concentrated andthe resulting residue dissolved in ethyl acetate (200 mL) then washedsequentially with water (25 mL), 1N HCl (25 mL), water (25 mL) and brine(25 mL). The combined aqueous layers were extracted with CH₂Cl₂ (3×50mL). The combined organic phases were dried (Na₂SO₄), filtered,concentrated and purified by flash chromatography (SiO₂), using 30–50%ethyl acetate/Hexanes as eluent to afford the title compound (0.331 g,14% yield) as a yellow powder. ¹H NMR (500 MHz, CDCl₃) δ: 7.48–7.45 (1H,m), 7.88 (2H, d, J=7.9 Hz), 7.30 (2H, d, J=7.0 Hz), 7.12 (2H, t, J=7.6Hz), 7.05–7.01 (1H, m), 5.22 (2H, s), 4.77 (2H, s), 4.06 (4H, s), 1.59(6H, s). HRMS (M+H) calcd for C₂₅H₂₃FN₃O₅: 464.1622; found: 464.1628.

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A 25 mL round-bottom flask was charged with intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid, (0.991 g, 3.0 mmol), intermediate 39,2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt(1.185 g, 4.0 mmol), 4-dimethylaminopyridine (DMAP, 1.1 g, 9.0 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 1.722 g, 4.5 mmol). Dimethylformamide (20 mL)was added and the mixture stirred for 1 h at ambient temperature. Afterthis, the reaction mixture was diluted with ethyl acetate (100 mL) thenwashed with water (3×25 mL) and brine (25 mL). The organic layer wasdried (Na₂SO₄), filtered, concentrated and purified by flashchromatography (SiO₂), eluting with hexanes/ethyl acetate (1:1 to 1:3)followed by ethyl acetate, to afford the title compound as an off-whitesolid (1.48 g, 100% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm: 8.49 (1H, t,J=6.1 Hz), 7.48–7.46 (2H, m), 7.43 (1H, dd, J=8.5, 5.5 Hz), 7.31–7.27(3H, m), 7.12 (1H, dd, J=8.9, 2.7 Hz), 7.05 (1H, td, J=8.2, 2.7 Hz),6.52 (1H, br s), 5.26 (2H, s), 4.53 (2H, d, J=6.4 Hz), 4.01 (2H, t,J=4.9 Hz), 3.96 (2H, t, J=4.9 Hz), 2.97 (3H, d, J=4.9 Hz), 1.62 (6H, s).HRMS (M+H) calcd for C₂₆H₂₈FN₄O₅: 495.2044. found: 495.2032.

N-(4-Fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid, (1.50 g, 4.54 mmol) and HATU (2.07 g, 5.45 mmol) in anhydrousdimethylformamide was stirred for 20 minutes under a nitrogen atmosphereat room temperature. To the solution was added intermediate 135,2-hydroxy-4-fluoro-benzylamine hydrochloride, (1.05 g, 5.9 mmol)followed by DMAP (1.39 g, 11.4 mmol), and the reaction mixture stirredat 60° C. for 90 minutes. The solvent was removed in vacuo and the cruderesidue purified by flash column chromatography (SiO₂), eluting with40%–60% ethyl acetate in hexanes to give the title compound (1.31 g, 64%yield) as a solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 9.69 (1H, br s), 8.18(1H, t, J=6.3 Hz), 7.44 (2H, dd, J=6.6, 2.6 Hz), 7.30–7.35 (3H, m), 7.00(1H, dd, J=8.2, 6.7 Hz), 6.68 (1H, dd, J=10.4, 2.4 Hz), 6.54 (1H, dt,J=8.2, 2.4 Hz), 5.29 (2H, s), 4.36 (2H, d, J=6.7 Hz), 3.97–4.05 (4H, m),1.61 (6H, s).

N-(4-Fluoro-2-(2-oxopiperidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazin-4(9H)-one. To intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid, (80 mg, 0.242 mmol) in CH₃CN/dimethylformamide (5 mL: 1 mL:) wasadded intermediate 125,1-(2-(aminomethyl)-5-fluorophenyl)piperidin-2-one hydrochloride salt,(69 mg, 0.266 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP) (139 mg, 0.266 mmol) anddiisopropylethylamine (169 μL, 0.968 mmol). The reaction mixture wasstirred at 23° C. for 3 h. The solvents were then removed in vacuo andan aqueous solution of HCl (1N, 25 mL) was added. This was extractedwith ethyl acetate (3×25 mL). The combined organic fractions were dried(MgSO₄), filtered and concentrated in vacuo. The crude material waspurified on a Biotage system using a silica gel column withHexanes/ethyl acetate (1:1) to (1:5) as eluent to afford 114 mg (88%yield) of the title compound. ¹HNMR 400 MHz (DMSO) δ ppm: 8.73 (1H, dd,(t), J=6.0 Hz), 7.46 (2H, m), 7.35 (4H, m), 7.18 (1H, dd, J=9.8, 3.0 Hz)7.0 (1H, m), 5.10 (2H, s), 4.43 (1H, dd, J=15.0, 7.08 Hz), 4.06 (1H, dd,J=15.0, 5.56), 4.02 (2H, t, J=5.0 Hz), 3.90 (2H, t, J=5.0 Hz), 3.64 (1H,m), 3.44 (1H, m), 2.45 (1H, m), 2.35 (1H, m), 1.86 (4H, m), 1.56 (6H,s). LCMS (M+H)⁺ m/z 535.

N-(4-Fluoro-2-(2-oxoazetidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid, (0.142 g, 0.430 mmol) in CH₃CN: dimethylformamide (30 mL: 5 mL)was added intermediate 120,1-(2-(aminomethyl)-5-fluorophenyl)azetidin-2-one hydrochloride, (0.100g, 0.43 mmol), (benzotriazole-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (0.207 g, 0.470 mmol) and diisopropylethylamine (280μL, 1.72 mmol). The reaction mixture was stirred at 23° C. for 18 h. Thesolvents were removed in vacuo and 1N HCl (50 mL) added. This wasextracted with ethyl acetate (2×50 mL). The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified on a Biotage system using a silica gel column with ethylacetate as eluent to afford the title compound (0.157 g, 72% yield). ¹HNMR (400 MHz, MeOD) δ ppm: 7.88 (1H, d, J=8.3 Hz), 7.76 (1H, d, J=8.0Hz), 7.58–7.30 (4H, m), 7.10 (1H, dd, J=10.2, 2.5 Hz), 6.90 (1H, m),5.20 (2H, s), 4.55 (2H, s), 4.04 (2H, m), 3.96 (2H, m), 3.78 (2H, t,J=4.2 Hz), 3.10 (2H, t, J=4.2 Hz), 1.58 (6H, s); LCMS (M+H)⁺ m/z 506.

N-(Benzo[b]thiophen-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid (0.200 g, 0.60 mmol) in CH₃CN:dimethylformamide (30 mL: 5 mL) wasadded intermediate 139, benzo[b]thiophen-7-ylmethanamine hydrochloride(0.069 g, 0.266 mmol),benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP) (0.347 g, 0.670 mmol) and diisopropylethylamine (420 μL, 2.40mmol). The reaction mixture was stirred at 23° C. for 60 h. The solventswere then removed in vacuo and 1N HCl (50 mL) added. This was extractedwith ethyl acetate (2×50 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified ona Biotage system using a silica gel column with hexane:ethyl acetate(1:1) to (1:5) gradient as eluent to afford the title compound (0.279 g,87% yield): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.11 (1H, dd, J=5.6 Hz), 7.81(1H, m), 7.77 (1H, d, J=5.6 Hz), 7.52 (1H, d, J=5.6 Hz), 7.48–7.26 (6H,m), 5.09 (2H, s), 4.67 (2H, d, J=5.2 Hz), 4.04 (2H, m), 3.90 (2H, m),1.58 (6H, s), LCMS (M+H)⁺ m/z 476.

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide.A solution of intermediate 35,3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylicacid in anhydrous dimethylformamide (4 mL) was treated with HATU (0.278g, 0.70 mmol) and stirred for 10 minutes. The reaction mixture wastreated with 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroaceticacid salt (0.24 g, 0.8 mmol), followed by dimethylaminopyridine (0.121g, 0.97 mmol), then stirred for 4 hours at 60° C. Following this, thesolvent was removed in vacuo and the remaining residue dissolved inethyl acetate (15 mL) and washed with 1.0 N HCl (15 mL). The organiclayer was dried (sodium sulfate), filtered, and concentrated to dryness.The crude product was purified by flash column chromatography (SiO₂),eluting with ethyl acetate. Fractions containing the product werepooled, concentrated to dryness and triturated with ether to provide0.366 g of the title compound as a white glassy solid. ¹H NMR (500 MHz,d₆-acetone) δ ppm: 8.71–8.82 (1H, m), 7.84–7.95 (1H, br), 7.47–7.62 (4H,m), 7.27–7.40 (5H, m), 7.20 (1H, dt, J=8.5, 2.7 Hz), 5.15–5.21 (2H,4.48–4.60 (4H, m), 2.96 (2H, s), 2.94 (2H, s), 1.62–1.64 (6H, s).

Intermediates 149–174

Intermediates 149–174 were prepared according to the coupling proceduresdescribed for intermediates 140–148.

N-(4-Fluorobenzyl)-3-(benzyloxy)-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 16,3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid and 4-fluorobenzylamine. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.67 (3H,d, J=6.6 Hz, CH₃), 3.91 (2H, m, CH₂), 4.12–4.35 (2H, m, CH₂), 4.52 (2H,d, J=5.9 Hz, NCH₂), 4.70 (1H, q, J=6.6 Hz, OCH), 5.33 (2H, s, OCH₂),7.02 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.35 (3H, m,aromatics), 7.47 (2H, m, aromatics), 7.71 (1H, broad t, NH).

N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate7,3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide.White crystals; mp 189–190° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 3.01 (3H, d, J=4.5 Hz, NCH₃), 4.00 (2H, m, CH₂), 4.08 (1H, m,CH), 4.50 (2H, d, J=6.6 Hz, NCH₂), 4.71 (2H, s, OCH₂), 5.38 (2H, s,OCH₂), 6.88 aromatic), 7.30–7.44 (6H, m, aromatics), 8.55 (1H, broad t,NH). Anal. Calcd for C₂₄H₂₃FN₄O₅: C, 61.80; H, 4.97; N, 12.01. Found: C,61.84; H, 4.82; N, 12.00.

N-(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid which was synthesized using the method described for the synthesisor intermediates 7 and 16, and intermediate 69,(4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine. White needles; mp155–157° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.03 (3H, t,J=7.5 Hz, CH₃), 1.97–2.02 (1H, m, CH), 2.29–2.32 (1H, m, CH), 3.83–3.88(2H, m, CH₂), 4.15–4.31 (2H, m, CH₂), 4.44 (2H, m, CH₂), 4.53 (1H, m,CH), 5.34 (2H, s, OCH₂), 7.08 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic),7.20 (1H, m, aromatic), 7.29–7.31 (3H, m, aromatics), 7.47 (2H, m,aromatics), 7.74 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.02 (1H, s,CH), 8.41 (1H, s, CH), 8.55 (1H, broad t, NH). Anal. Calcd forC₂₆H₂₅FN₆O₄: C, 61.89; H, 4.99; N, 16.65. Found: C, 61.67; H, 5.13; N,16.61.

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 85,(4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. Whitecrystals; mp 203° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm):1.65 (6H, s, 2×CH₃), 2.50 (3H, s, CH₃), 4.03 (4H, m, 2×CH₂), 4.46 (2H,d, J=6.6 Hz, NCH₂), 5.31 (2H, s, OCH₂), 7.06 (1H, dd, J=3 Hz and J=8.6Hz, aromatic), 7.16 (1H, m, aromatic), 7.30–7.34 (3H, m, aromatics),7.50 (2H, m, aromatics), 7.74 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic),8.28 (1H, s, CH), 8.45 (1H, broad t, NH). Anal. Calcd for C₂₇H₂₇FN₆O₄:C, 62.54; H, 5.25; N, 16.21. Found: C, 62.48; H, 5.31; N 16.29.

N-(2-Fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 87,(2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. Whitecrystals; mp 183–185° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm):1.65 (6H, s, 2×CH₃), 2.52 (3H, s, CH₃), 4.05 (4H, m, 2×CH₂), 4.64 (2H,d, J=6.1 Hz, NCH₂), 5.33 (2H, s, OCH₂), 7.29–7.55 (8H, m, aromatics),7.84 (1H, broad t, NH), 8.45 (1H, s, CH). Anal. Calcd for C₂₇H₂₇FN₆O₄:C, 62.54; H, 5.25; N, 16.21. Found: C, 62.41; H, 5.40; N, 16.23.

Methyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoate.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 38, methyl 2-(aminomethyl)-5-fluorobenzoate. ¹HNMR (CDCl₃, 500 MHz) δ ppm: 1.61 (6H, s, gem-Me), 3.88 (3H, s, OMe),3.97 (2H, t, J=5.5 Hz, CH₂), 4.02 (2H, t, J=5.5 Hz, CH₂), 4.73 (2H, d,J=6.7 Hz, NCH₂), 5.25 (2H, s, OCH₂), 7.19 (1H, dt, J=3, 8.5 Hz, Ar—H),7.27–7.31 (3H, m, Ar—Hs), 7.48–7.50 (2H, m, Ar—Hs), 7.61 (1H, dd, J=5.5,8.5 Hz, Ar—H), 7.66 (1H, dd, J=3, 9.5 Hz, Ar—H). LC/MS m/z 496 (M+H).

N-(2-(Cyclopropylcarbamoyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 40,2-(aminomethyl)-N-cyclopropyl-5-fluorobenzamide. LC/MS m/z 521 (M+H).

N-(4-Fluoro-2-(morpholine-4-carbonyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 44,(2-(aminomethyl)-5-fluorophenyl)(morpholino)methanone. ¹H NMR (CDCl₃,500 MHz) δ ppm: 1.59 (6H, s), 3.29 (2H, brs), 3.57 (2H, m), 3.74 (4H,s), 3.98 (4H, m), 5.26 (2H, s), 6.88 (1H, dd, J=8.2, 2.7 Hz), 7.03 (1H,dt, J=8.5, 2.5 Hz), 7.24–7.33 (3H, m), 7.42 (2H, dd, J=8.6, 5.3 Hz),7.47 (2H, dd, J=7.5, 2.0 Hz), 8.18 (1H, t, J=6.4 Hz); LC/MS m/z 551(M+H).

N-(4-Fluoro-2-(2-morpholino-2-oxoethoxy)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 131,2-(2-(aminomethyl)-5-fluorophenoxy)-1-morpholinoethanone. ¹H NMR (CDCl₃,500 MHz) δ ppm: 1.59 (6H, s, gem-Me), 3.38, 3.54 (4H, br, NCH₂), 3.62(4H, m, OCH₂), 3.96 (2H, m, NCH₂), 4.01 (2H, m, OCH₂), 4.55 (2H, s,OCH₂), 4.55 (2H, d, J=4.3 Hz, NCH₂), 5.17 (2H, s, OCH₂), 6.53 (1H, dd,J=10, 2.1 Hz, Ar—H), 6.63 (1H, dt, J=2.5, 8 Hz, Ar—H), 7.23–7.26 (1H, m,Ar—H), 7.28–7.30 (3H, m, Ar—Hs), 7.42–7.44 (2H, m, Ar—Hs), 8.00 (1H, t,J=5.5 Hz, NH); ¹³C NMR (CDCl₃, 125.77 Hz) δ ppm: 27.74, 38.76, 42.30,42.98, 45.38, 58.06, 66.55, 66.78, 66.91, 74.72, 76.27, 100.40, 100.61,108.07, 108.23, 122.56, 128.37, 128.49, 128.84, 130.88, 130.96, 139.69,141.36, 141.98, 156.70, 157.02, 157.10, 159.58, 162.04, 163.99, 162.86,165.79. HRMS (ESI) calcd for C₃₀H₃₄N₄O₇F (M+H) 581.2412. Found 581.2393.

Dimethyl-carbamic acid2-{[(3-benzyloxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-pyrimido[2,1-c][1,4]oxazine-2-carbonyl)-amino]-methyl}-5-fluoro-phenylester. The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and intermediate 133, 2-(aminomethyl)-5-fluorophenyldimethylcarbamate. ¹H NMR (CDCl₃, 500 MHz) δ ppm: 1.58 (6H, s, gem-Me),2.92, 3.05 (2s, NMe), 3.96 (2H, m, NCH₂), 4.00 (2H, m, OCH₂), 4.48 (2H,d, J=5.5 Hz, NCH₂), 5.26 (2H, s, OCH₂), 6.84 (1H, dd, J=2.5 Hz, 9 Hz,Ar—H), 6.87 (1H, dt, J=2.5 Hz, 8 Hz, Ar—H), 7.25–7.33 (4H, m, Ar—Hs),7.53 (2H, d, J=˜7 Hz, Ar—Hs), 7.78 (1H, brt, J=5 Hz, NH); ¹³C NMR(CDCl₃, 125.77 Hz) δ ppm: 27.68, 36.61, 36.89, 37.97, 42.97, 58.06,74.73, 76.23, 110.58, 110.77, 113.06, 113.23, 126.55, 126.58, 128.31,128.45, 128.91, 131.23, 131.31, 136.76, 140.70, 142.00, 150.60, 150.69,154.50, 156.30, 159.79, 161.40, 163.37, 162.43. HRMS (ESI) calcd forC₂₇H₃₀N₄O₆F (M+H) 525.2149. Found 525.2163.

N-(4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 1-(2-(aminomethyl)-5-fluorophenyl)pyrrolidin-2-one, derivedfrom reduction of intermediate 111,4-fluoro-2-(2-oxopyrrolidin-1-yl)benzonitrile. ¹HNMR 400 MHz (MeOD) δppm: 7.44 (3H, m), 7.33 (3H, m), 7.11 (1H, dd, J=9.2, 3.0 Hz) 7.03 (1H,m), 5.21 (2H, s), 4.43 (2H, s), 4.08 (2H, t, J=5.0 Hz), 3.98 (2H, t,J=5.0 Hz), 3.85 (2H, t, J=7.1 Hz), 2.58 (2H, t, J=8.0 Hz), 2.23 (2H, m),1.61 (6H, s). LCMS (M+H)⁺ m/z 521.

N-(4-Fluoro-2-(2-oxoazepan-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2carboxamide. The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 1-(2-(aminomethyl)-5-fluorophenyl)azepan-2-one, derived fromreduction of intermediate 113,4-fluoro-2-(2-oxoazepan-1-yl)benzonitrile. ¹HNMR 400 MHz (DMSO) δ ppm:8.80 (1H, dd, (t), J=6.0 Hz), 7.46 (2H, m), 7.36 (4H, m), 7.08 (1H, dd,J=9.8, 2.8 Hz), 7.0 (1H, m), 5.09 (2H, s), 4.43 (1H, dd, J=15.2, 7.1Hz), 4.06 (1H, dd, J=15.2, 5.0 Hz), 4.02 (2H, t, J=5.0 Hz), 3.90 (2H, t,J=5.0 Hz), 3.77 (1H, m), 3.51 (1H, m), 2.70 (1H, m), 2.51 (2H, m), 1.76(6H, m), 1.56 (6H, s). LCMS (M+H)⁺ m/z 549.

N-(2-(2-Oxooxazolidin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 3-(2-(aminomethyl)phenyl)oxazolidin-2-one, derived fromreduction of intermediate 116, 2-(2-oxooxazolidin-3-yl)benzonitrile. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 8.90 (1H, t, J=6.0 Hz), 7.58–7.32 (7H, m),7.22 (2H, t, J=7.5 Hz), 5.08 (2H, s), 4.48 (2H, t, J=7.8 Hz), 4.44 (2H,d, J=6.0 Hz), 4.06–3.97 (4H, m), 3.88 (2H, m), 1.56 (6H, s); LCMS (M+H)⁺m/z 505.

N-(2-(2-Oxoazetidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 1-(2-(aminomethyl)phenyl)azetidin-2-one, derived from reductionof intermediate 115, 2-(2-oxoazetidin-1-yl)benzonitrile. ¹H NMR (400MHz, CDCl₃) δ ppm: 8.67 (1H, brt, J=6.3 Hz), 7.60 (1H, dd, J=1.3, 7.6Hz), 7.53–7.50 (1H, dd, m), 7.34–7.24 (5H, m), 7.18 (1H, ddd(dt), J=1.2,7.4 Hz), 7.10 (1H, dd, J=1.2, 8.0 Hz), 5.27 (2H, s), 4.60 (2H, d, J=6.3Hz), 4.01–3.95 (4H, m), 3.71 (2H, t, J=4.5 Hz), 3.10 (2H, t, J=4.5 Hz),1.60 (6H, s); LCMS (⁺ESI, M+H⁺) m/z 489.

N-(4-Fluoro-2-(thiazol-2-ylamino)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and N-(2-(aminomethyl)-5-fluorophenyl)thiazol-2-amine, derived fromreduction of intermediate 123,4-fluoro-2-(thiazol-2-ylamino)benzonitrile. ¹H NMR (400 MHz, DMSO-d₆) δppm: 9.92 (1H, s), 9.10 (1H, t, J=6.3 Hz), 8.19 (1H, dd, J=2.8, 12.3Hz), 7.41–7.38 (2H, m), 7.32–7.28 (5H, m), 6.99 (1H, d, J=3.8 Hz), 6.71(1H, ddd(dt), J=2.8, 8.3), 5.05 (2H, s), 4.45 (2H, d, J=6.3 Hz),4.01–3.98 (2H, m), 3.88–3.85 (2H, m), 1.54 (6H, s) LCMS (⁺ESI, M+H⁺) m/z536.

N-(4-Fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid andN-(2-(aminomethyl)-5-fluorophenyl)-5-methyl-1,3,4-thiadiazol-2-amine,derived from reduction of intermediate 124,4-fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzonitrile. LCMS(⁺ESI, M+H⁺) m/z 551.

N-(4-Fluoro-2-(2-oxooxazolidin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 3-(2-(aminomethyl)-5-fluorophenyl)oxazolidin-2-one, derivedfrom reduction of intermediate 117,4-fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile. ¹H NMR (400 MHz, MeOD) δppm: 9.48 (1H, dd, J=8.6, 6.5 Hz), 7.41 (2H, m), 7.32 (3H, m), 7.22 (1H,dd, J=9.6, 2.5 Hz), 7.08 (1H, td, J=8.6, 2.7 Hz), 5.21 (2H, s), 4.57(2H, t, J=7.7 Hz), 4.50 (2H, s), 4.07 (4H, m), 3.99 (2H, m), 1.61 (6H,s). LCMS (M+H)⁺ m/z 523.

(R)—N-(2-(2-((tert-Butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and(S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one,derived from reduction of intermediate 122,(R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile¹HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.47 (2H, m), 7.35 (4H,m), 7.00 (1H, broad s), 5.09 (2H, s), 4.60–4.10 (3H, m), 4.02 (3H, m),3.88 (2H, m), 3.53 (2H, broad s), 2.42–2.35 (2H, m), 1.94 (1H, m), 1.56(3H, s), 1.55 (3H, s), 0.82 (9H, broad s), −0.01 (6H, s). LCMS (M+H)⁺m/z 665.

(S)—N-(2-(2-((tert-Butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and(S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one,derived from reduction of intermediate 121,(R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile.¹HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.52–7.33 (7H, m), 7.02(1H, broad s), 5.60 (2H, s), 4.60–4.20 (2H, m), 4.02 (3H, t, J=5.0 Hz),3.89 (3H, t, 5.0 Hz), 3.53 (2H, broad s), 2.51 (2H, s), 2.44–2.26 (2H,m), 1.94 (1H, broad s), 1.57 (3H, s), 1.55 (3H, s), 0.82 (9H, broad s),−0.02 (6H, s). LCMS (M+H)⁺ m/z 665.

N-(4-Fluoro-2-(N-methylacetamido)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid N-(2-(aminomethyl)-5-fluorophenyl)-N-methylacetamide, derived fromreduction of intermediate 114,N-(2-cyano-5-fluorophenyl)-N-methylacetamide. ¹HNMR 400 MHz (MeOD) δppm: 7.49–7.33 (6H, m), 7.15–7.06 (2H, m), 5.22 (2H, s), 4.41 (2H d,J=2.4 Hz), 4.09 (2H, t, J=5.1 Hz), 4.01 (2H, t, J=5.1 Hz), 3.25 (0.4H,s), 3.22 (2.6H, s), 1.85 (3H, s), 1.63 (6H, s). LCMS (M+H)⁺ m/z 509.

N-(2-Amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid 2-(aminomethyl)-5-fluorobenzenamine. ¹HNMR 400 MHz (MeOD) δ ppm:¹HNMR 400 MHz (MeOD) δ ppm: 7.36 (2H, m), 7.30 (3H, m), 7.10 (1H, dd,J=8.3, 6.5 Hz), 6.47 (1H, dd, J=11.1, 2.5 Hz), 6.32 (1H, ddd, (dt),J=8.6, 2.5 Hz), 5.19 (2H, s), 4.40 (2H, s), 4.07 (2H, t, J=5.0 Hz), 3.99(2H, t, J=5.0 Hz), 1.61 (6H, s). LCMS (M+H)⁺ m/z 453.

N-(2-(Ethylamino)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and 2-(aminomethyl)-N-ethyl-5-fluorobenzenamine. ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.27 (3H, t, J=7.1 Hz, CH₃), 1.63 (6H, s, 2×CH₃), 3.10(2H, q, J=7.1 Hz, CH₂), 4.04 (4H, m, 2×CH₂), 4.45 (2H, d, J=6.6 Hz,NCH₂), 5.27 (2H, s, OCH₂), 6.28 (1H, broad s, aromatic), 6.31 (1H, m,aromatic), 6.98 (1H, m, aromatic), 7.3–7.38 (3H, m, aromatics), 7.49(2H, m, aromatics), 7.54 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₆H₃₀FN₄O₄ [M+H⁺]: 481.2251. Found: 481.2254.

N-(4-Fluorobenzyl)-3-(benzyloxy)-N-methoxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and (4-fluorophenyl)-N-methoxymethanamine. White crystals; mp 141°C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.66 (6H, s,2×CH₃), 3.59 (3H, s, OCH₃), 4.07 (4H, m, 2×CH₂), 4.90 (2H, s, NCH₂),5.20 (2H, s, OCH₂), 6.81 (2H, m, aromatics), 7.26–7.30 (3H, m,aromatics), 7.36 (2H, m, aromatics), 7.44 (2H, m, aromatics). HRMS(ESI⁺) calculated for C₂₅H₂₇FN₃O₅ [M+H⁺]: 468.1935. Found: 468.1916.

N-(4-Fluoro-2-(1,2,3-thiadiazol-4-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and (4-fluoro-2-(1,2,3-thiadiazol-4-yl)phenyl)methanamine. ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.66 (6H, s, 2×CH₃), 4.02 (4H, m, 2×CH₂), 4.57(2H, d, J=6.6 Hz, NCH₂), 5.32 (2H, s, OCH₂), 7.18 (1H, m, aromatic),7.27–7.34 (4H, m, aromatics), 7.54 (2H, m, aromatics), 7.74 (1H, dd,J=6.2 Hz and J=8.6 Hz, aromatic), 8.71 (1H, s, CH), 8.80 (1H, broad t,NH). HRMS (ESI⁺) calculated for C₂₆H₂₅FN₅O₄S [M+H⁺]: 522.1611. Found:522.1601.

N-(4-Fluoro-2-(5-methyloxazol-2-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and (4-fluoro-2-(5-methyloxazol-2-yl)phenyl)methanamine. Whitecrystals; mp 186° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.61 (6H, s, 2×CH₃), 2.43 (3H, s, CH₃), 4.02 (4H, m, 2×CH₂), 4.80(2H, d, J=6.3 Hz, NCH₂), 5.25 (2H, s, OCH₂), 6.82 (1H, s, CH), 7.11 (1H,m, aromatic), 7.29–7.34 (3H, m, aromatics), 7.52 (2H, m, aromatics),7.65 (1H, dd, J=2.5 Hz and J=9.6 Hz, aromatic), 7.69 (1H, dd, J=6.1 Hzand J=8.6 Hz, aromatic), 9.32 (1H, broad t, NH). HRMS (ESI⁺) calculatedfor C₂₈H₂₈FN₄O₅ [M+H⁺]: 519.2044. Found: 519.2024.

N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 27,3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylicacid and (4-fluoro-2-iodophenyl)methanamine. White solid. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.66 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH_(2,)), 4.57 (2H,d, J=6.6 Hz, NCH₂), 7.05 (1H, m, aromatic), 7.3–7.38 (3H, m, aromatics),7.42 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.53 (2H, m, aromatics),7.56 (1H, dd, J=2.6 Hz and J=8.0 Hz, aromatic), 8.05 (1H, broad t, NH).HRMS (ESI⁺) calculated for C₂₄H₂₄FIN₃O₄ [M+H⁺]: 564.0796. Found:564.0809.

N-(4-Fluoro-2-(2-methoxypyridin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.Intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.350 g, 0.62 mmol) in a mixture of acetonitrile (12 ml) and water (12ml) was treated with 2-methoxypyridin-3-ylboronic acid (0.190 g, 1.24mmol), sodium carbonate (0.20 g, 1.88 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.15 g). The reaction mixturewas degassed, flushed with argon and heated at 90° C. for 30 min. Thereaction mixture was then diluted with ethyl acetate, washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated.Chromatography of the residue on silica gel (elution gradient of ethylacetate in hexane) gave 0.245 g (72% yield) of the title material as awhite solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 3.89 (3H,s, OCH₃), 4.04 (4H, m, 2×CH₂), 4.37 (2H, broad, NCH₂), 5.26 (2H, s,OCH₂), 6.93 (1H, dd, J=2.5 Hz and J=9 Hz, aromatic), 7.0 (1H, dd, J=5 Hzand J=7 Hz, aromatic), 7.06 (1H, m, aromatic), 7.3–7.5 (8H, m, aromaticsand NH), 8.24 (1H, m, aromatic). HRMS (ESI⁺) calculated for C₃₀H₃₀FN₄O₅[M+H⁺]: 545.2200. Found: 545.2184.

N-(4-Fluoro-2-phenyl-benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.Intermediate 174,N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.266 mmol) in a mixture of acetonitrile (10 ml) and water (10ml) was treated with phenylboronic acid (0.042 g, 0.35 mmol), sodiumcarbonate (0.062 g, 0.58 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.070 g). The reaction mixturewas degassed, flushed with argon and heated at 90° C. for 30 min. Thereaction mixture was then diluted with ethyl acetate, washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated.Chromatography of the residue on silica gel (elution gradient of ethylacetate in hexane) gave 0.124 g (91% yield) of the title material as alight yellow solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.61 (6H, s, 2×CH₃),4.03 (4H, m, 2×CH₂), 4.49 (2H, d, J=6.1 Hz, NCH₂), 7.02 (2H, m,aromatics), 7.29–7.51 (12H, m, aromatics and NH). HRMS (ESI⁺) calculatedfor C₃₀H₂₉FN₃O₄ [M+H⁺]: 514.2142. Found: 514.2137.

N-(4-Fluoro-2-(1H-pyrazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.Intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.27 mmol) was reacted with 1H-pyrazol-5-ylboronic acid (0.060g, 0.54 mmol), sodium carbonate (0.085 g, 0.81 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.070 g) to give 0.085 g (62%yield) of the title material as a white solid after chromatography onsilica gel. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.63 (6H, s, 2×CH₃), 4.03(4H, m, 2×CH₂), 4.65 (2H, d, J=6.5 Hz, NCH₂), 5.25 (2H, s, OCH₂), 6.54(1H, d, J=2.5 Hz, CH), 7.03 (1H, m, aromatic), 7.25 (1H, dd, J=2.5 Hzand J=9.8 Hz, aromatic), 7.35 (3H, m, aromatics), 7.53 (2H, m,aromatics), 7.56 (1H, d, J=2.5 Hz, CH), 7.60 (1H, dd, J=6.1 Hz and J=8.6Hz, aromatic), 8.96 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₇H₂₇FN₅O₄ [M+H⁺]: 504.2047. Found: 504.2068.

N-(4-Fluoro-2-(2-(trimethylsilyl)ethynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.277 g, 0.49 mmol) in a mixture of N,N-dimethylformamide (3 ml) andpiperidine (1.2 ml) was treated under argon withdichlorobis(triphenylphosphine)palladium(II) (0.020 g),triphenylphosphine (0.010 g), copper(1) iodide (0.010 g) followed by(trimethylsilyl)acetylene (0.21 ml, 1.47 mmol). The resulting mixturewas sealed and heated at 50° C. for one hour. The reaction mixture wasthen diluted with ethyl acetate, washed with water and brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure.Chromatography of the residue on silica gel (elution gradient of ethylacetate in hexane) gave 0.164 g (63% yield) of the title material as alight yellow solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 0.27 (9H, s, SiCH₃),1.64 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂), 4.71 (2H, d, J=6.1 Hz=NCH₂),5.32 (2H, s, OCH₂), 6.99 (1H, m, aromatic), 7.19 (1H, dd, J=2.6 Hz andJ=9.1 Hz, aromatic), 7.3–7.37 (4H, m, aromatics), 7.48–7.51 (2H, m,aromatics), 7.75 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₉H₃₃FN₃O₄Si [M+H⁺]: 534.2224. Found: 534.2229.

N-(2-Ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 178,N-(4-fluoro-2-(2-(trimethylsilyl)ethynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.28 mmol) in methanol (5 ml) was treated with potassiumcarbonate (0.120 g, 0.84 mmol) and the resulting mixture stirred at 22°C. for one hour. The reaction mixture was then diluted with ethylacetate, washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give 0.129 g (100%yield) of the title material as a light yellow solid. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.64 (6H, s, 2×CH₃), 3.31 (1H, s, CH), 4.04 (4H, m,2×CH₂), 4.69 (2H, d, J=6.6 Hz, NCH₂), 5.31 (2H, s, OCH₂), 7.04 (1H, m,aromatic), 7.21 (1H, dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.32–7.42(3H, m, aromatics), 7.40 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic),7.52–7.54 (2H, m, aromatics), 8.00 (1H, broad t, NH). HRMS (ESI⁺)calculated for C₂₆H₂₅FN₃O₄ [M+H]: 462.1829. Found: 462.1822.

N-(4-Fluoro-2-(3-methylisoxazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 179,N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.32 mmol) in dimethyl sulfoxide (5 ml) was treated withnitromethane (0.14 ml, 1.92 mmol),4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM) (0.241 g, 1.0 mmol) (M. Kunishima et al., Tetrahedron, 55, 1999,13159–13170) and 4-(dimethylamino)pyridine (DMAP) (0.010 g) and theresulting mixture stirred at 22° C. for 16 h. Identical quantities ofnitromethane, DMTMM and DMAP were then added and the mixture was stirredfor another 24 h. The reaction mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate and brine, then dried overanhydrous magnesium sulfate and concentrated under reduced pressure.Chromatography of the residue on silica gel (elution gradient of ethylacetate in dichloromethane) gave 0.122 g (73% yield) of the titlematerial as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.62 (6H, s,2×CH₃), 2.39 (3H, s, CH₃), 4.04 (4H, m, 2×CH₂), 4.69 (2H, d, J=6.1 Hz,NCH₂), 5.31 (2H, s, OCH₂), 6.36 (1H, m, CH), 7.13 (1H, m, aromatic),7.30–7.35 (4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.58 (1H,dd, J=5.5 Hz and J=8.6 Hz, aromatic), 8.06 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₈H₂₈FN₄O₅ [M+H⁺]: 519.2044. Found: 519.2059.

N-(2-(3-Bromoisoxazol-5-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 179,N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.350 g, 0.76 mmol) in a mixture of ethyl acetate (10 ml) and water (2ml) was treated with potassium bicarbonate (0.230 g, 2.3 mmol) followedby dibromoformaldoxime (0.354 g, 1.75 mmol) (D. M. Vyas, Y. Chiang andT. W. Doyle, Tetrahedron Letters, 1984, 25, 487–490) and the resultingmixture stirred at 22° C. After 1 h, identical quantities of potassiumbicarbonate and dibromoformaldoxime were added and the mixture stirredfor another 1.5 h. The reaction mixture was then diluted with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. Crystallization of the residue fromether gave 0.300 g (68% yield) of the title material as a white solid.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂),4.67 (2H, d, J=6.6 Hz, NCH₂), 5.32 (2H, s, OCH₂), 6.60 (1H, s, CH), 7.17(1H, m, aromatic), 7.30–7.36 (4H, m, aromatics), 7.51–7.53 (2H, m,aromatics), 7.60 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 8.01 (1H,broad t, NH). HRMS (ESI⁺) calculated for C₂₇H₂₅BrFN₄O₅ [M+H⁺]: 583.0992.Found: 583.0986.

N-(4-Fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.Reaction of intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.563 g, 1.00 mmol) with propargyl alcohol (0.18 ml, 3.2 mmol) usingthe conditions described for intermediate 178 gave 0.415 g (85% yield)of the title material as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm:1.64 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂), 4.39 (2H, d, J=6.6 Hz, CH₂),4.68 (2H, d, J=6.0 Hz, CH₂), 5.29 (2H, s, OCH₂), 6.99 (1H, m, aromatic),7.13 (1H, dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.22 (1H, dd, J=5.6 Hzand J=8.6 Hz, aromatic), 7.33–7.37 (3H, m, aromatics), 7.44–7.47 (2H, m,aromatics), 7.68 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₇H₂₇FN₃O₅ [M+H⁺]: 492.1935. Found: 492.1939.

3-[2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynylmethanesulfonate. A solution of intermediate 182,N-(4-fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.280 g, 0.57 mmol) and triethylamine (0.12 ml, 0.86 mmol) indichloromethane (5 ml) was cooled to 0° C., treated drop wise withmethanesulfonyl chloride (0.050 ml, 0.64 mmol) and then stirred for 30min. The reaction mixture was then diluted with ethyl acetate, washedwith saturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. Chromatography of theresidue on silica gel (elution gradient of ethyl acetate in hexane) gave0.245 g (75% yield) of the title material as a white solid. ¹HNMR 400MHz (CDCl₃) δ ppm: 1.65 (6H, s, 2×CH₃), 3.10 (3H, s, SCH₃), 4.05 (4H, m,2×CH₂), 4.67 (2H, d, J=6.1 Hz, NCH₂), 5.03 (2H, s, CH₂), 5.29 (2H, s,OCH₂), 7.07 (1H, m, aromatic), 7.18 (1H, dd, J=2.5 Hz and J=9.1 Hz,aromatic), 7.32–7.36 (3H, m, aromatics), 7.38 (1H, dd, J=5.5 Hz andJ=8.6 Hz, aromatic), 7.49–7.51 (2H, m, aromatics), 7.77 (1H, broad t,NH). MS (ESI⁺) m/e 570 [M+H⁺].

N-(2-(3-(Dimethylamino)prop-1-ynyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 183,3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynylmethanesulfonate (0.100 g, 0.18 mmol) in acetonitrile (5 ml) was treatedat 22° C. with 0.3 ml (0.6 mmol) of a 2 M solution of dimethylamine intetrahydrofuran and the resulting mixture was stirred for 30 min. Thereaction mixture was then diluted with ethyl acetate, washed withsaturated sodium bicarbonate, brine, then dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give 0.080 g (88%yield) of the title material as a white solid. ¹HNMR 400 MHz (CDCl₃) δppm: 1.64 (6H, s, 2×CH₃), 2.43 (6H, s, 2×NCH₃), 3.58 (2H, broad s, CH₂),4.05 (4H, m, 2×CH₂), 4.70 (2H, d, J=6.0 Hz, NCH₂), 5.30 (2H, s, OCH₂),7.01 (1H, m, aromatic), 7.18 (1H, dd, J=3 Hz and J=9.1 Hz, aromatic),7.32–7.38 (4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.79 (1H,broad t, NH). HRMS (ESI⁺) calculated for C₂₉H₃₂FN₄O₄ [M+H⁺]: 519.2408.Found: 519.2407.

N-(4-Fluoro-2-(3-(methylthio)prop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of intermediate 183,3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynylmethanesulfonate (0.160 g, 0.28 mmol) in N,N-dimethylformamide (3 ml)was treated at 0° C. with sodium thiomethoxide (0.026 g, 0.37 mmol) andthe resulting mixture stirred for 2 h. The reaction mixture was thendiluted with ethyl acetate, washed with saturated sodium bicarbonate andbrine, then dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. Chromatography of the residue on silica gel(elution gradient of ethyl acetate in hexane) gave 0.114 g (78% yield)of the title material as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm:1.64 (6H, s, 2×CH₃), 2.28 (3H, s, SCH₃), 3.45 (2H, s, SCH₂), 4.05 (4H,m, 2×CH₂), 4.69 (2H, d, J=6.1 Hz, NCH₂), 5.31 (2H, s, OCH₂), 6.98 (1H,m, aromatic), 7.15 (1H, dd, J=3 Hz and J=9.1 Hz, aromatic), 7.32–7.38(4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.80 (1H, broad t,NH). HRMS (ESI⁺) calculated for C₂₈H₂₉FN₃O₄S [M+H⁺]: 522.1863. Found:522.1844.

N-(4-Fluoro-2-(3-(methylsulfonyl)prop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c[], 4]oxazine-2-carboxamide. A solution of intermediate 185,N-(4-fluoro-2-(3-(methylthio)prop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.110 g, 0.21 mmol) in dichloromethane (3 ml) was treated at 0° C. with3-chloroperoxybenzoic acid (0.120 g of 85%, 0.59 mmol) and the resultingmixture was stirred at 22° C. for 30 min. The reaction mixture was thendiluted with ethyl acetate, washed with saturated sodium bicarbonate,brine, then dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. Chromatography of the residue on silica gel(elution gradient of ethyl acetate in dichloromethane) gave 0.074 g (64%yield) of the title material as a white solid. ¹HNMR 400 MHz (CDCl₃) δppm: 1.64 (6H, s, 2×CH₃), 3.03 (3H, s, SCH₃), 4.03 (2H, s, SCH₂), 4.05(4H, m, 2×CH₂), 4.65 (2H, d, J=6.0 Hz, NCH₂), 5.27 (2H, s, OCH₂), 7.06(1H, m, aromatic), 7.17 (1H, dd, J=3 Hz and J=8.6 Hz, aromatic),7.31–7.38 (6H, m, aromatics), 8.12 (1H, broad t, NH). HRMS (ESI⁺)calculated for C₂₈H₂₉FN₃O₆S [M+H⁺]: 554.1761. Found: 554.1784.

Diethyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.A solution of intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.200 g, 0.35 mmol) and triphenylphosphine (0.020 mg) in ethanol (5 ml)was flushed with argon and then treated with N,N-diisopropylethylamine(0.25 ml, 1.4 mmol), palladium(11) acetate (0.020 g) and diethylphosphite (0.15 ml, 1.16 mmol). The reaction mixture was then sealed andheated at 80° C. for 18 h. The reaction mixture was then diluted withethyl acetate, washed with 0.1 N hydrochloric acid, saturated sodiumbicarbonate, brine, then dried over anhydrous magnesium sulfate andconcentrated. Chromatography of the residue on silica gel (elutiongradient of acetonitrile in dichloromethane) gave 0.103 g (51% yield) ofthe title compound as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.36(6H, t, J=6.6 Hz, 2×CH₃), 1.64 (6H, s, 2×CH₃), 4.04 (4H, m, 2×CH₂),4.08–4.22 (4H, m, 2×OCH₂), 4.78 (2H, d, J=6.6 Hz, NCH₂), 5.29 (2H, s,OCH₂), 7.21 (1H, m, aromatic), 7.29–7.34 (3H, m, aromatics), 7.45–7.52(3H, m, aromatics), 7.65–7.72 (1H, m, aromatic), 8.67 (1H, broad t, NH).HRMS (ESI⁺) calculated for C₂₈ H₃₄FN₃O₇P [M+H⁺]: 574.2118. Found:574.2126.

Ethyl hydrogen2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.A solution of intermediate 187, diethyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate(0.115 g, 0.20 mmol) in tetrahydrofuran (3 ml)/ethanol (3 mL) wastreated with 1 N aqueous sodium hydroxide (1.0 ml, 1.0 mmol) and theresulting mixture heated at 45° C. for 2 h. The reaction mixture wasthen diluted with ethyl acetate, washed with 0.1 N hydrochloric acid,brine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified on a Shimadzu automated preparative HPLC system(column YMC Pack C-18, 5μ, 20×250 mm, elution gradientacetonitrile-water 0.1% trifluoroacetic acid) to give 0.070 g (64%yield) of the title material as a clear oil. ¹HNMR 400 MHz (CDCl₃) δppm: 1.37 (3H, t, J=7.1 Hz, CH₃), 1.62 (6H, s, 2×CH₃), 4.04 (4H, m,2×CH₂), 4.18 (2H, m, OCH₂), 4.75 (2H, broad d, J=5 Hz, NCH₂), 5.32 (2H,s, OCH₂), 7.21 (1H, m, aromatic), 7.30–7.33 (3H, m, aromatics),7.38–7.40 (2H, m, aromatics), 7.47–7.52 (1H, m, aromatic), 7.56–7.63(1H, m, aromatic), 8.56 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₆H₃₀FN₃O₇P [M+H⁺]: 546.1805. Found: 546.1786.

N-(2-Acetamido-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 169,N-(2-amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.033 g, 0.073 mmol) in dry tetrahydrofuran (10 mL) was added acetylchloride (5.7 μL, 0.08 mmol) and diisopropylethylamine (38 μL, 0.22mmol). The reaction mixture was stirred at 23° C. for 3 h. NaHCO₃ (0.25M, 20 mL) was then added and the organic material extracted with ethylacetate (3×25 mL). The organic extracts were combined, dried (MgSO₄) andconcentrated in vacuo. The residue was purified on a Biotage systemusing a silica gel column with ethyl acetate:Hex (1:2 to 2:1) as eluentto afford the title compound (0.025 g, 69% yield). ¹HNMR 400 MHz (MeOD)δ (ppm): 7.66 (1H, dd, J=10.5, 2.8 Hz), 7.43–7.25 (6H, m), 6.87 (1H,ddd, (dt), J=8.8, 2.6 Hz), 5.19 (2H, s), 4.47 (2H, m), 4.08 (2H, t,J=4.9 Hz), 3.99 (2H, t, J=4.9 Hz), 2.19 (3H, s), 1.62 (6H, s). LCMS(M+H)⁺ m/z 495.

2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoicacid. To a suspension of intermediate 154, methyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoate.(500 mg, 1.01 mmol) in MeOH (10 mL) and CH₃CN (5 mL) was added 1N NaOH(2 mL) and the mixture stirred at room temperature for 2 hrs. Themixture was concentrated in vacuo and the residue purified by reversephase column chromatography (YMC, C-18 ODS, 10–25% CH₃CN/H₂O) to provide90 mg (Yield 19%) of the title compound as an off-white powder: LC/MSm/z 482 (M+H).

N-(2-((2-Aminoethyl)carbamoyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A mixture of intermediate 190,2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoicacid, (59 mg, 0.12 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, HATU (76 mg, 0.2 mmol; Aldrich) in DMF (1 mL) wasstirred for 20 min. To this mixture was added ethanolamine (20 mg, 0.3mmol) and the stirring continued overnight. The mixture was concentratedin vacuo, dissolved in CH₂Cl₂, washed with water then dried (MgSO₄),filtered, and concentrated to provide 55 mg (Yield 87%) of the titlecompound: LC/MS m/z 525 (M+H).

(R)-N-(4-Fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a stirred solution of intermediate 166,(R)-N-(2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.10 g, 0.150 mmol) in tetrahydrofuran (5 mL) at 23° C. was added asolution of tetrabutylammonium fluoride (1M in tetrahydrofuran) (180 μL,0.18 mmol). The reaction mixture was stirred at 23° C. for 3 h. NaHCO₃(1N in H₂O, 30 mL) was then added and the organic material was extractedwith ethyl acetate (2×25 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified ona Biotage system using a silica gel column with ethyl acetate/Hexanes(1:1) to ethyl acetate 100% as eluent to afford the title compound(0.060 g, 73% yield): ¹HNMR 400 MHz (MeOD) δ (ppm): 7.55 (1H, dd, (t),6.6 Hz), 7.43 (2H, m), 7.13 (1H, dd, J=9.5, 2.4 Hz), 7.03 (1H, m), 5.26(2H, s), 4.57 (1H, m), 4.32 (2H, m), 4.08 (2H, t, J=5.0 Hz), 7.03 (2H,t, J=5.0 Hz), 3.53 (2H, m), 2.69–2.56 (2H, m), 2.38 (1H, m), 2.22 (1H,m), 1.62 (6H, s). LCMS (M+H)⁺ m/z 551.

(R)-(1-(2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methylacetate. To a solution of intermediate 192,(R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.045 g, 0.082 mmol) in tetrahydrofuran (5 mL) was added acetylchloride (12.8 μL, 0.180 mmol) and diisopropylethylamine (31.4 μL, 0.180mmol). The reaction mixture was stirred at 23° C. for 4 h. NaHCO₃ (1N inH₂O, 30 mL) was then added and the organic material was extracted withethyl acetate (2×25 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified ona Biotage system using a silica gel column with ethyl acetate/Hexanes(1:1) to ethyl acetate 100% as eluent to afford the title compound(0.032 g, 67% yield): ¹HNMR 400 MHz (MeOD) δ ppm: 7.48 (3H, m), 7.33(3H, m), 7.16 (1H, m), 7.03 (1H, m), 5.24 (2H, s), 4.60 (1H, m), 4.55(1H, m), 4.22 (1H, dd, J=12.0, 4.5 Hz), 4.08 (2H, t, J=5.0 Hz), 3.99(3H, m), 2.62 (2H, m), 2.44 (1H, m), 2.09–1.92 (5H, m), 1.62 (3H, s),1.61 (3H, s). LCMS (M+H)⁺ m/z 593.

(R)-(1-(2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methylmethanesulfonate. To a stirred solution of intermediate 192,(R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.160 g, 0.291 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added triethylamine(81 μL, 0.582 mmol) and methanesulfonyl chloride (27 μL, 0.349 mmol).The reaction mixture was stirred at 23° C. for 4 h. Water (50 mL) wasthen added and the organic material was extracted with CH₂Cl₂ (2×50 mL).The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo to afford the title compound (0.178 g, 98% yield).The crude material was used without further purification for the nextstep: LCMS (M+H)⁺ m/z 629.

(R)-N-(2-(2-(Azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 194,(R)-(1-(2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methylmethanesulfonate (0.150 g, 0.239 mmol) in DMF (10 mL) was added sodiumazide (0.019 g, 0.287 mmol). The resulting mixture was stirred at 50° C.for 6 h. Water (50 mL) was then added and the organic material wasextracted with ethyl acetate (2×50 mL). The combined organic extractswere washed with H₂O (50 mL), dried (MgSO₄), filtered and concentratedin vacuo to afford the title compound (0.125 g, 91% yield). LCMS (M+H)⁺m/z 576.

N-(Benzo[b]thiophen-1,1-dione-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 147,N-(benzo[b]thiophen-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.100 g, 0.21 mmol) in dichloroethane (10 mL) was added per-acetic acid(32% in H₂O) (1.0 mmol, 200 μL). The reaction mixture was stirred at 23°C. for 48 h. Water (50 mL) was added and the organic material wasextracted with CH₂Cl₂ (2×50 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo to afford the titlecompound (0.106 g, 99% yield): ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.11(1H, t, J=6.4 Hz), 7.65 (1H, d, J=6.8 Hz) 7.59–7.29 (9H, m), 5.15 (2H,s), 4.77 (2H, d, J=6.5 Hz), 4.04 (2H, t, J=5.0 Hz), 3.90 (2H, m), 1.59(6H, s). LCMS (M+H)⁺ m/z 508.

EXAMPLE 1

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-. Amixture of intermediate 7, ethyl3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.036 g, 0.15 mmol) and 4-fluorobenzylamine (0.11 g, 0.87 mmol) inanhydrous ethyl alcohol (5 ml) and N,N-dimethylformamide (2 ml) washeated under reflux for 18 h. The solvent was then evaporated in vacuoand the residue was partitioned between ethyl acetate and 0.1 Nhydrochloric acid. The organic phase was washed with water, brine anddried over anhydrous sodium sulfate. Evaporation of the solvent andrecrystallization of the resulting solid from ethanol gave 0.023 g (47%yield) of the title amide as white crystals; mp 211° C. (ethylacetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 4.06 (4H, m, 2×CH₂), 4.59(2H, d, J=7.6 Hz, NCH₂), 4.61 (2H, s, OCH₂), 7.09 (2H, m, aromatics),7.33 (2H, m, aromatics), 7.84 (1H, broad t, NH), 12.06 (1H, s, OH). MS(ESI⁺) m/z-320 [M+H⁺].

EXAMPLE 2

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.Reaction of intermediate 7, ethyl3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.100 g, 0.42 mmol) with 4-fluoro-3-methylbenzylamine (0.23 g, 1.66mmol) as described in the preparation of example 1 gave 0.101 g (73%yield) of the title amide as white crystals; mp 206–208° C. (ethylacetate). ¹HNMR 400 MHz (CDCl₃) δ ppm: 2.30 (3H, s, CH₃), 4.06 (4H, m,2×CH₂), 4.55 (2H, d, J=6.1 Hz, NCH₂), 4.60 (2H, s, OCH₂), 7.01 (1H, m,aromatic), 7.14 (2H, m, aromatics), 7.81 (1H, broad t, NH), 12.09 (1H,s, OH). MS (ESI⁺) m/z 334 [M+H⁺].

EXAMPLE 3

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from intermediate 150,N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (DMSO-d₆) δ ppm: 2.79 (3H, d, J=4.5 Hz, NCH₃), 3.83 (2H,m, CH₂), 4.02 (2H, m, CH₂), 4.54 (2H, d, J=6.7 Hz, NCH₂), 4.58 (2H, s,OCH₂), 7.31 (2H, m, aromatics), 7.38 (1H, m, aromatic), 8.54 (1H, broadq, NH), 9.21 (1H, broad t, NH), 12.24 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₇H₁₈FN₄O₅ [M+H⁺]: 377.1261. Found: 377.1249.

EXAMPLE 4

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(0.050 g, 0.20 mmol) with 4-fluorobenzylamine (0.11 g, 0.87 mmol) asdescribed in the preparation of example 1 gave 0.056 g (84% yield) ofthe title amide as white crystals; mp 165–167° C. (ethylacetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.62 (3H, d, J=7.0 Hz,CH₃), 3.90 (2H, m, CH₂), 4.15–4.32 (2H, m, CH₂), 4.61 (3H, m, NCH₂ andOCH), 7.08 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.82 (1H, broadt, NH), 12.06 (1H, s, OH). Anal. Calcd for C₁₆H₁₆FN₃O₄: C, 57.65; H,4.83; N, 12.60. Found: C, 57.44; H, 4.69; N, 12.37.

EXAMPLE 5

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.090 g, 0.35 mmol) with 4-fluoro-3-methylbenzylamine (0.180 g, 1.3mmol) as described in the preparation of example 1 gave 0.068 g (55%yield) of the title amide as white crystals; mp 134° C. (ethylacetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.62 (3H, d, J=6.6 Hz,CH₃), 2.30 (3H, s, CH₃), 3.90 (2H, m, CH₂), 4.13–4.32 (2H, m, CH₂),4.49–4.64 (3H, m, NCH₂ and OCH), 7.01 (1H, m, aromatic), 7.16 (2H, m,aromatics), 7.79 (1H, broad t, NH), 12.09 (1H, s, OH). Anal. Calcd forC₁₇H₁₈FN₃O₄: C, 58.78; H, 5.22; N, 12.09. Found: C, 58.57; H, 5.55; N,11.90.

EXAMPLE 6

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dichlorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(0.075 g, 0.29 mmol) with 3,4-dichlorobenzylamine (0.140 g, 0.8 mmol) asdescribed in the preparation of example 1 gave 0.085 g (75% yield) ofthe title amide as white crystals; mp 192° C. (ethyl acetate-hexane).¹HNMR 400 MHz (CDCl₃) δ ppm: 1.64 (3H, d, J=6.6 Hz, CH₃), 3.91 (2H, m,CH₂), 4.17–4.32 (2H, m, CH₂), 4.50–4.68 (3H, m, NCH₂ and OCH), 7.20 (1H,dd, J=2.0 Hz and J=8.0 Hz, aromatic), 7.44 (1H, d, J=2.0 Hz, aromatic),7.46 (1H, d, J=8.0 Hz, aromatic), 7.86 (1H, broad t, NH), 11.92 (1H, s,OH). MS (ESI⁺) m/z 384 [M+H⁺]. Anal. Calcd for C₁₆H₁₅Cl₂N₃O₄: C, 50.02;H, 3.94; N, 10.94. Found: C, 49.40; H, 4.06; N, 10.41.

EXAMPLE 7

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-chloro-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.075 g, 0.30 mmol) with 3-chloro-4-fluorobenzylamine (0.14 g, 0.88mmol) as described in the preparation of example 1 gave 0.050 g (46%yield) of the title amide as white crystals; mp 172° C. (ethylacetate-ether). ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (3H, d, J=6.6 Hz,CH₃), 3.91 (2H, m, CH₂), 4.17–4.32 (2H, m, CH₂), 4.50–4.67 (3H, m, NCH₂and OCH), 7.16 (1H, m, aromatic), 7.24 (1H, m, aromatic), 7.40 (1H, m,aromatic), 7.85 (1H, broad t, NH), 11.95 (1H, s, OH). Anal. Calcd forC₁₆H₁₅ClFN₃O₄: C, 52.25; H, 4.11; N, 11.42. Found: C, 51.99; H, 4.01; N,11.09.

EXAMPLE 8

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.Reaction of intermediate 15, ethyl3-hydroxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.075 g, 0.30 mmol) with 3,4-dimethylbenzylamine (0.15 g, 1.1 mmol) asdescribed in the preparation of example 1 gave 0.033 g (33% yield) ofthe title amide as a white solid. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.61 (3H,d, J=6.6 Hz, CH₃), 2.28 (3H, s, CH₃), 2.29 (3H, s, CH₃), 3.90 (2H, m,CH₂), 4.16–4.30 (2H, m, CH₂), 4.50–4.65 (3H, m, NCH₂ and OCH), 7.08–7.17(3H, m, aromatics), 7.78 (1H, broad t, NH), 12.17 (1H, s, OH). MS (ESI⁺)m/z 344 [M+H⁺].

EXAMPLE 9

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-methyl-4-oxo-.A solution of intermediate 140,N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.268 g, 0.56 mmol) in a mixture of ethyl acetate (25 ml) and ethanol(25 ml) was hydrogenated under 1 atm of hydrogen at 25° C. over 10%palladium on activated carbon (0.09 g) for 2.5 h to give 0.121 g (56%yield) of the title ester as a white solid. ¹HNMR 400 MHz (DMSO-d₆) δppm: 1.57 (3H, d, J=6.7 Hz, CH₃), 2.79 (3H, d, J=4.6 Hz, NCH₃), 3.70(1H, m, CH), 3.87 (1H, m, CH), 3.98 (1H, m, CH), 4.15 (1H, m, CH), 4.55(2H, m, NCH₂), 4.62 (1H, q, J=6.6 Hz, OCH), 7.25–7.44 (3H, m,aromatics), 8.59 (1H, broad q, NH), 9.39 (1H, broad, NH), 12.18 (1H, s,OH). HRMS (ESI⁺) calculated for C₁₈H₂₀FN₄O₅ [M+H⁺]: 391.1418. Found:391.1431.

EXAMPLES 10–14

Examples 10–14 can be prepared from ethyl9-ethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the method described for thesynthesis of example 1. Ethyl9-ethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylatewas prepared according to the method used to prepare intermediate 15.

EXAMPLE 10

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from 4-fluorobenzylamine. ¹HNMR 400MHz (CDCl₃) δ ppm: 1.02 (3H, t, J=7.3 Hz, CH₃), 1.93 (1H, m, CH), 2.15(1H, m, CH), 3.88 (2H, m, CH₂), 4.2–4.29 (2H, m, CH₂), 4.46 (1H, m, CH),4.53–4.69 (2H, m, CH₂), 7.06 (2H, m, aromatics), 7.34 (2H, m,aromatics), 7.82 (1H, broad t, NH), 12.05 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₇H₁₉FN₃O₄ [M+H⁺]: 348.1360. Found: 348.1355.

EXAMPLE 11

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from(4-fluoro-3-methylphenyl)methanamine. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.01(3H, t, J=7.4 Hz, CH₃), 1.91 (1H, m, CH), 2.16 (1H, m, CH), 2.30 (3H, s,CH₃), 3.87 (2H, m, CH₂), 4.2–4.30 (2H, m, CH₂), 4.46 (1H, m, CH),4.48–4.65 (2H, m, CH₂), 7.01 (1H, m, aromatic), 7.14 (2H, m, aromatics),7.81 (1H, broad t, NH), 12.07 (1H, s, OH). Anal. Calcd for C₁₈H₂₀FN₃O₄:C, 59.82, H, 5.57, N, 11.62; Found: C, 59.53; H, 5.86; N, 11.42.

EXAMPLE 12

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dichlorophenyl)methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from (3,4-dichlorophenyl)methanamine.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.00 (3H, t, J=7.3 Hz, CH₃), 1.91 (1H, m,CH), 2.15 (1H, m, CH), 3.85 (2H, m, CH₂), 4.19–4.28 (2H, m, CH₂), 4.45(1H, m, CH), 4.48–4.66 (2H, m, CH₂), 7.19 (1H, m, aromatic), 7.43 (2H,m, aromatics), 7.84 (1H, broad t, NH), 11.88 (1H, s, OH). Anal. Calcdfor C₁₇H₁₇Cl₂N₃O₄: C, 51.27; H, 4.30; N, 10.55. Found: C, 51.16; H,4.21; N, 10.34.

EXAMPLE 13

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dimethylphenyl)methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from (3,4-dimethylphenyl)methanamine.¹HNMR 400 MHz (CDCl₃) δ ppm: 0.98 (3H, t, J=7.3 Hz, CH₃), 1.87 (1H, m,CH), 2.12 (1H, m, CH), 2.26 (3H, s, CH₃), 2.27 (3H, s, CH₃), 3.83 (2H,m, CH₂), 4.17–4.26 (2H, m, CH₂), 4.41 (1H, m, CH), 4.45–4.64 (2H, m,CH₂), 7.05–7.24 (3H, m, aromatics), 7.75 (1H, broad t, NH), 12.13 (1H,s, OH). Anal. Calcd for C₁₉H₂₃N₃O₄: C, 63.85; H, 6.49; N, 11.76. Found:C, 63.55; H, 6.48; N, 11.74.

EXAMPLE 14

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-chloro-4-fluorophenyl)methyl]-9-ethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from(3-chloro-4-fluorophenyl)methanamine. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.03(3H, t, J=7.3 Hz, CH₃), 1.92 (1H, m, CH), 2.17 (1H, m, CH), 3.88 (2H, m,CH₂), 4.18–4.32 (2H, m, CH₂), 4.46 (1H, m, CH), 4.5–4.68 (2H, m, CH₂),7.16 (1H, m, aromatic), 7.24 (1H, m, aromatic), 7.40 (1H, m, aromatic),7.84 (1H, broad t, NH), 11.93 (1H, s, OH). Anal. Calcd forC₁₇H₁₇ClFN₃O₄: C, 53.48; H, 4.48; N, 11.00. Found: C, 53.25; H, 4.49; N,10.79.

EXAMPLES 15–16

Examples 15–16 can be prepared from3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid and the indicated amines according to the methods described for thesynthesis of intermediate 140 and example 9.3-(Benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylicacid was prepared according to the method used to prepare intermediate16.

EXAMPLE 15

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from intermediate 39. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.03 (3H, t, J=7.3 Hz, CH₃), 1.98 (1H, m, CH), 2.28 (1H,m, CH), 3.06 (3H, d, J=4.5 Hz, NCH₃), 3.86 (2H, m, CH₂), 4.14–4.29 (2H,m, CH₂), 4.48 (1H, m, CH), 4.60 (2H, m, CH₂), 6.2 (1H, broad, NH),7.14–7.21 (2H, m, aromatics), 7.54 (1H, m, aromatic), 8.85 (1H, broad t,NH), 12.1 (1H, s, OH). HRMS (ESI⁺) calculated for C₁₉H₂₂FN₄O₅ [M+H⁺]:405.1574. Found: 405.1579.

EXAMPLE 16

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9-ethyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from intermediate 151,N-(4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,according to a procedure similar to that described in example 9. ¹HNMR400 MHz (DMSO-d₆) δ ppm: 0.94 (3H, t, J=7.5 Hz, CH₃), 1.88 (1H, m, CH),2.27 (1H, m, CH), 3.68 (1H, m, CH), 3.87 (1H, m, CH), 4.0 (1H, m, CH),4.19 (1H, m, CH), 4.36–4.49 (3H, m, CH₂ and CH), 7.43 (1H, m, aromatic),7.56 (2H, m, aromatics), 8.32 (1H, m, CH), 9.05 (1H, m, CH), 9.3 (1H,broad t, NH), 12.04 (1H, s, OH). HRMS (ESI⁺) calculated for C₁₉H₂₀FN₆O₄[M+H⁺]: 415.1530. Found: 415.1515.

EXAMPLES 17–18

Examples 17–18 can be prepared from ethyl3-hydroxy-9-isopropyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the method described for thesynthesis of example 1. Ethyl3-hydroxy-9-isopropyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylatecan be prepared according to the method used to prepare intermediate 15.

EXAMPLE 17

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-(1-methylethyl)-4-oxo-.The title compound can be prepared from 4-fluorobenzylamine. ¹HNMR 400MHz (CDCl₃) δ ppm: 0.80 (3H, d, J=6.7 Hz, CH₃), 1.13 (3H, d, J=7.1 Hz,CH₃), 2.54 (1H, m, CH), 3.77 (2H, m, CH₂), 4.3 (2H, m, CH₂), 4.40 (1H,d, J=2.5 Hz, CH), 4.50–4.72 (2H, m, CH₂), 7.09 (2H, m, aromatics), 7.34(2H, m, aromatics), 7.82 (1H, broad t, NH), 12.04 (1H, s, OH). Anal.Calcd for C₁₈H₂₀FN₃O₄: C, 59.82; H, 5.57; N, 11.62. Found: C, 59.22, H,5.81, N, 11.50.

EXAMPLE 18

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-(1-methylethyl)-4-oxo-.The title compound can be prepared from(4-fluoro-3-methylphenyl)methanamine. ¹HNMR 400 MHz (CDCl₃) δ ppm: 0.80(3H, d, J=6.6 Hz, CH₃), 1.13 (3H, d, J=7.1 Hz, CH₃), 2.30 (3H, s, CH₃),2.54 (1H, m, CH), 3.77 (2H, m, CH₂), 4.3 (2H, m, CH₂), 4.40 (1H, broads, CH), 4.46–4.68 (2H, m, CH₂), 7.02 (1H, m, aromatic), 7.17 (2H, m,aromatics), 7.80 (1H, broad t, NH), 12.07 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₉H₂₃FN₃O₄ [M+H⁺]: 376.1673. Found: 376.1671.

EXAMPLE 19

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To a solution of intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(3.0 g, 11.19 mmol) in DMF (20 mL) and ethanol (10 mL) was addedtriethylamine (1.55 mL) followed by 4-fluorobenzylamine (3.82 mL, 33.57mmol). The mixture was stirred at 90° C. for 2 h and then concentrated.The resultant oil was partitioned between ethyl acetate (50 mL) and 1Naqueous HCl (35 mL). The aqueous layer was back-extracted with ethylacetate (20 mL) and the organic layers were combined and washed with H₂O(4×20 mL) and brine then dried (Na₂SO₄) and concentrated. The brownresidue was triturated with ether and the solids filtered and washedwith ether. The pale brown solids were recrystallized from 95:5 MeOH/H₂Oto give the title compound as colorless needles (3.18 g, 82% yield). ¹HNMR (500 MHz, CDCl₃) δ ppm: 11.96 (1H, s), 7.77 (1H, brs), 7.30 (2H, dd,J=8.4, 5.3 Hz), 7.04 (2H, t, J=8.7 Hz), 4.57 (2H, d, J=6.1 Hz), 4.01(4H, s), 1.56 (6H, s). HRMS (M+H) calcd for C₁₇H₁₉FN₃O₄: 348.13597.Found: 348.1365. Anal calcd for C₁₇H₁₈FN₃O₄: C, 58.78; H, 5.22; N,12.09. Found: C, 58.38; H, 5.23; N, 11.80.

EXAMPLE 20

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A DMF solution of intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(4 mL, 1 mmol), Et₃N (0.14 mL, 1 mmol) and 3-methy-4-fluorobenzylamine(0.418 g, 3 mmol) was heated at 90° C. for 5 h. The reaction mixture wascooled and the product isolated by reverse phase preparative HPLC usingMeOH/H₂O—0.1% CF₃CO₂H as eluent. The fractions containing the desiredmaterial were combined and concentrated to afford the title compound asa yellow powder (0.19 g, 52% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm:11.99 (1H, s), 7.73 (1H, s), 7.14 (1H, d, J=7.3 Hz), 7.12–7.09 (1H, m),6.98 (1H, t, J=9.0 Hz), 4.54 (2H, d, J=6.4 Hz), 4.01 (4H, s), 2.27 (3H,s), 1.56 (6H, s). HRMS (M+H) calcd for C₁₈H₂₁FN₃O₄: 362.1516. Found:362.1509. Anal calcd for C₁₈H₂₀FN₃O₄+0.07H₂O: C, 59.26; H, 5.55; N,11.48. Found: C, 58.88; H, 5.36; N, 11.34.

EXAMPLES 21–41

Examples 21–41 can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,and the indicated amines according to the method described for thesynthesis of examples 1, 19 and 20.

EXAMPLE 21

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 69. Solid, ¹H NMR(500 MHz, DMSO-d₆) δ ppm: 11.93 (1H, s), 9.29 (1H, t, J=6.2 Hz), 9.05(1H, s), 8.32 (1H, s), 7.57–7.53 (2H, m), 7.43 (1H, td, J=7.9, 1.7 Hz),4.44 (2H, d, J=6.1 Hz), 3.98 (2H, t, J=4.9 Hz), 3.83 (2H, t, J=4.9 Hz),1.56 (6H, s). HRMS (M+H) calcd for C₁₉H₂₀N₆O₄F: 415.15302. Found:415.1520. Anal Calcd for C₁₉H₁₉N₆O₄F: C, 55.07; H, 4.62; N, 20.28; F,4.58. Found: C, 54.95; H, 4.67; N, 20.27; F, 4.56.

EXAMPLE 22

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 70. Solid, ¹H NMR(500 MHz, DMSO-d₆) δ ppm: 12.07 (1H, s), 9.46 (1H, bs), 9.33 (1H, s),8.26 (1H, s), 7.81 (1H, dd, J=11.1, 2.0 Hz), 7.73 (1H, dd, J=8.2, 1.8Hz), 7.52 (1H, t, J=8.2 Hz), 4.59 (2H, d, J=6.1 Hz), 3.98 (2H, t, J=5.0Hz), 3.84 (2H, t, J=5.0 Hz), 1.58 (6H, s). HRMS (M+H) calcd forC₁₉H₂₀N₆O₄F: 415.15302. Found: 415.1520. Anal calcd forC₁₉H₁₉N₆O₄F+1.25H₂O: C, 52.23; H, 4.96; N, 19.23; F, 4.35. Found: C,52.29; H, 4.66; N, 19.23; F, 4.35.

EXAMPLE 23

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(4-morpholinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 73. Solid, ¹H NMR(500 MHz, CDCl₃) δ ppm: 12.09 (1H, s), 7.91 (1H, brs), 7.31–7.28 (1H,m), 6.90 (1H, dd, J=10.4, 2.4 Hz), 6.84 (1H, td, J=8.1, 2.4 Hz), 4.66(2H, d, J=6.4 Hz), 4.02 (4H, s), 3.89–3.87 (4H, m), 2.94–2.92 (4H, m),1.59 (6H, s). HRMS (M−H) calcd for C₂₁H₂₄N₄O₅F: 431.17307. Found:431.1719. Anal calcd for C₂₁H₂₅N₄O₅F: C, 58.32; H, 5.82; N, 12.95; F,4.39. Found: C, 58.13; H, 5.81; N, 12.79; F, 4.33.

EXAMPLE 24

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-fluoro-4-(4-morpholinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 74. ¹H NMR (500MHz, CDCl₃) δ ppm: 12.01 (1H, s), 7.80 (1H, brs), 7.28–7.24 (1H, m),6.66 (1H, d, J=8.5 Hz), 6.61 (1H, dd, J=13.4, 1.8 Hz), 4.56 (2H, d,J=6.1 Hz), 4.01 (4H, s), 3.85–3.84 (4H 3.17–3.15 (4H, m), 1.60 (6H, s).HRMS (M−H) calcd for C₂₁H₂₄N₄O₅F: 431.17307. Found: 431.1729. Anal calcdfor C₂₁H₂₅N₄O₅F: C, 58.32; H, 5.82; N, 12.95; F, 4.39. Found: C, 58.23;H, 5.73; N, 12.82; F, 4.21.

EXAMPLE 25

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[3-(3,4-dichlorophenyl)propyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from3-(3,4-dichlorophenyl)propan-1-amine. ¹H NMR (500 MHz, CDCl₃) δ ppm:12.05 (1H, s), 7.46 (1H, brs), 7.35 (1H, d, J=8.2 Hz), 7.28 (1H, d,J=2.1 Hz), 7.04 (1H, dd, J=8.2, 2.1 Hz), 4.02 (4H, s), 3.46 (2H, q,J=6.9 Hz), 2.67 (2H, t, J=7.6 Hz), 1.95 (2H, m), 1.59 (6H, s). HRMS(M+H) calcd for C₁₉H₂₂N₃O₄Cl₂: 426.09875. Found: 426.0996. Anal calcdfor C₁₉H₂₁N₃O₄Cl₂: C, 53.53; H, 4.96; N, 9.85; Cl, 16.63; Found: C,53.57; H, 4.96; N, 9.76; Cl, 16.63.

EXAMPLE 26

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[3-(4-fluorophenyl)propyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from3-(4-fluorophenyl)propan-1-amine. ¹H NMR (500 MHz, CDCl₃) δ ppm: 12.09(1H, s), 7.15 (2H, dd, J=8.2, 5.5 Hz), 6.97 (2H, t, J=8.5 Hz), 4.02 (4H,s), 3.44 (2H, q, J=13.9, 6.9 Hz), 2.68 (2H, t, J=7.6 Hz), 1.98–1.92 (2H,m), 1.62 (6H, s). HRMS (M+H) calcd for C₁₉H₂₃N₃O₄F: 376.16727. Found:376.1687. Anal calcd for C₁₉H₂₂N₃O₄F: C, 60.79; H, 5.90; N, 11.19; F,5.06. Found: C, 60.70; H, 5.87; N, 11.14; F, 4.92.

EXAMPLE 27

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 76. ¹H NMR (500MHz, CDCl₃) δ ppm: 12.07 (1H, s), 8.31 (1H, d, J=6.44 Hz), 7.46 (1H, dd,J=8.5, 6.4 Hz), 7.19 (1H, dd, J=9.0, 2.6 Hz), 7.08 (1H, td, J=8.2, 2.7Hz), 4.92 (1H, dd, J=14.0, 8.8 Hz), 4.37 (1H, dd, J=14.0, 3.4 Hz),4.02–3.97 (2H, m), 3.99 (2H, s), 3.87–3.82 (1H, m), 3.45–3.41 (1H, m),3.30–3.20 (2H, m), 2.46–2.32 (2H, m), 2.00–1.88 (2H, m), 1.57 (3H, s),1.53 (3H, s). HRMS (M−H) calcd for C₂₁H₂₆N₄O₆FS: 481.15572. Found:481.1570. Anal calcd for C₂₁H₂₅N₄O₆FS: C, 52.49; H, 5.24; N, 11.66; F,3.95; S, 6.67. Found: C, 52.29; H, 5.37; N, 11.40; F, 3.91; S, 6.70.

EXAMPLE 28

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,5-difluoro-2-pyridinyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 102. ¹H NMR (500MHz, CDCl₃) δ ppm: 11.86 (1H, s), 8.58 (1H, brs), 8.33 (1H, d, J=2.4Hz), 7.27–7.24 (1H, m), 4.76 (2H, d, J=5.2 Hz), 4.03 (4H, s), 1.63 (6H,s). HRMS (M+H) calcd for C₁₆H₁₇F₂N₄O₄: 367.1218. Found: 367.1230.

EXAMPLE 29

N-((5-Chloropyridin-2-yl)methyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 103. ¹H NMR (500MHz, CDCl₃) δ ppm: 11.80 (1H, brs), 8.64 (1H, brs), 8.57 (1H, d, J=2.4Hz), 7.78 (1H, dd, J=8.6, 2.4 Hz), 7.44 (1H, d, J=8.6 Hz), 4.72 (2H, d,J=6.1 Hz), 4.02 (4H, s), 1.61 (6H, s). HRMS (M+H) calcd forC₁₇H₁₈ClN₄O₄: 365.1017. Found: 365.1028. Anal calcd forC₁₆H₁₇ClN₄O₄.0.25H₂O.0.5 CF₃CO₂H: C, 47.90; H, 4.26; N, 13.14; Cl, 8.32.Found C, 47.88; H, 3.98; N, 12.94, Cl, 8.57.

EXAMPLE 30

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-bromo-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(3-bromo-4-fluorophenyl)methanamine Off white solid, ¹H-NMR (500 MHz,CDCl₃) δ ppm: 11.88 (1H, s), 7.76–7.84 (1H, br), 7.53 (1H, dd, J=6.3,2.0 Hz), 7.26–7.29 (H, m), 7.07–7.14 (1H, m), 4.57 (2H, d, J=6.4 Hz),4.02 (4H, s), 1.58 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 168.41,157.79, 151.99, 146.52, 134.91, 132.89, 128.44, 128.39, 125.30, 117.04,116.86, 77.69, 75.84, 58.21, 43.22, 41.98, 28.11. HRMS [M+H]⁺ calcd forC₁₇H₁₈N₃O₄FBr: 426.04648. Found: 426.0468.

EXAMPLE 31

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (3,4-dimethylphenyl)methanamine.Off white solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.74 (1H), 7.04–7.15(3H, m), 4.56 (2H, d, J=5.8 Hz), 4.00–4.07 (4H, m), 2.27 (3H, s), 2.26(3H, s), 1.57 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 167.92, 158.58,151.61, 146.22, 137.37, 136.47, 134.53, 130.23, 129.11, 126.12, 125.12,75.93, 58.10, 43.42, 43.00, 28.04, 19.85, 19.53. HRMS [M+H]⁺ calcd forC₁₉H₂₄N₃O₄: 358.17669. Found: 358.1783.

EXAMPLE 32

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-chloro-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(3-chloro-4-fluorophenyl)methanamine. Off white solid, ¹H-NMR (500 MHz,CDCl₃) δ ppm: 11.88 (1H, br s), 7.80 (1H, t, J=5.5 Hz), 7.38 (1H, dd,J=6.7, 2.1 Hz), 7.19–7.23 (1H, m), 7.13 (1H, t, J=8.5 Hz), 4.57 (2H, d,J=6.4 Hz), 4.02 (4H, s), 1.58 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm:168.41, 157.82, 151.99, 146.52, 134.54, 130.02, 127.58, 127.52, 125.32,121.61, 117.18, 117.01, 75.84, 58.21, 43.23, 42.08, 28.11. HRMS [M+H]⁺calcd for C₁₇H₁₈N₃O₄FCl: 382.09644. Found: 382.0980.

EXAMPLE 33

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide, N-[(3,4-difluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (3,4-difluorophenyl)methanamine.Light brown solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.77 (1H), 7.30–7.36(2H, m), 7.27 (1H s), 4.59 (2H, d, J=6.4 Hz), 4.01–4.06 (4H, m), 1.58(6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 168.22, 158.36, 151.98, 151.17,146.35, 134.33, 125.74, 123.70, 123.67, 117.87, 117.73, 116.88, 116.73,75.90, 58.13, 43.42, 42.28, 28.06. HRMS [M+H]⁺ calcd for C₁₇H₁₈N₃O₄F₂:366.12655. Found: 366.1269.

EXAMPLE 34

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-chlorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (4-chlorophenyl)methanamine.Pale pink solid. ¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.77 (1H, br), 7.33–7.35(2H, m), 7.25–7.28 (2H, m), 4.59 (2H, d, J=6.4 Hz), 4.04 (4H, ddd,J=14.0, 7.9, 2.7 Hz), 1.58 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm:168.12, 158.48, 151.87, 146.28, 135.72, 133.98, 129.92, 129.18, 129.09,125.90, 75.92, 58.12, 43.45, 42.61, 28.06. HRMS [M+H]⁺ calcd forC₁₇H₁₉N₃O₄Cl: 364.10642. Found: 364.1060.

EXAMPLE 35

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,4-difluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (2,4-difluorophenyl)methanamine.Off white solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.86 (1H, t, J=5.6 Hz),7.34–7.40 (1H, m), 6.83–6.90 (2H, m), 4.62 (2H, d, J=6.4 Hz), 4.01–4.06(4H, m), 1.59 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 168.09, 158.43,151.81, 146.22, 131.30, 131.25, 131.22, 131.18, 125.87, 120.37, 120.34,111.85, 111.82, 111.68, 111.65, 104.47, 104.27, 104.07, 75.94, 58.12,43.43, 37.00, 28.07. HRMS [M+H]⁺ calcd for C₁₇H₁₈N₃O₄F₂: 366.12655.Found: 366.1281.

EXAMPLE 36

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-chloro-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(2-chloro-4-fluorophenyl)methanamine. Off white solid, ¹H-NMR (500 MHz,CDCl₃) δ ppm: 8.05 (1H, br), 7.41 (1H, dd, J=8.4, 6.0 Hz), 7.17 (1H, dd,J=8.2, 2.4 Hz), 6.99 (1H, td, J=8.2, 2.7 Hz), 4.66 (2H, d, J=6.4 Hz),4.04 (4H, s), 1.60 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 167.88,163.30, 161.31, 158.70, 151.77, 146.08, 134.55, 134.47, 131.65, 131.58,130.70, 130.67, 126.12, 117.48, 117.28, 114.68, 114.51, 109.67, 75.99,58.10, 43.51, 40.82, 28.08. HRMS [M+H]⁺ calcd for C₁₇H₁₈N₃O₄FCl:382.09644. Found: 382.0987.

EXAMPLE 37

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,4-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (2,4-dimethylphenyl)methanamine.Off white solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 12.08 (1H, brs), 7.63(1H, br), 7.15 (1H, d, J=7.6 Hz), 7.00–7.05 (2H, m), 4.57 (2H, d, J=5.8Hz), 4.01 (4H, s), 2.32 (3H, s), 2.32 (3H, s), 1.55 (6H, s). ¹³C-NMR(126 MHz, CDCl₃) δ ppm: 167.97, 157.98, 151.74, 146.35, 137.95, 136.22,131.90, 131.67, 128.38, 127.10, 125.64, 75.84, 58.21, 43.21, 41.15,28.07, 21.11, 19.13. HRMS [M+H]⁺ calcd for C₁₉H₂₄N₃O₄: 358.17669. Found:358.1771.

EXAMPLE 38

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,5-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from (3,5-dimethylphenyl)methanamine.Off white solid, ¹H-NMR (500 MHz, CDCl₃) δ ppm: 12.09 (1H, s), 7.72–7.80(1H, br), 6.95 (1H, s), 6.94 (2H, s), 4.55 (2H, d, J=6.4 Hz), 4.00–4.04(4H, s), 2.32 (6H, s), 1.57 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm:168.19, 157.89, 151.73, 146.44, 138.71, 137.25, 129.58, 125.61, 125.48,75.86, 58.23, 43.18, 43.06, 28.08, 21.38. HRMS [M+H]⁺ calcd forC₁₉H₂₄N₃O₄: 358.17669. Found: 358.1758.

EXAMPLE 39

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-. The title compound can be prepared from(4-fluoro-2-methylphenyl)methanamine. Off white solid, ¹H-NMR (500 MHz,CDCl₃) δ ppm: 11.97 (1H, s), 7.64 (1H, br), 7.23 (1H, dd, J=8.2, 5.8Hz), 6.87–6.94 (2H, m), 4.57 (2H, d, J=6.1 Hz), 4.02 (4H, s), 2.36 (3H,s), 1.56 (6H, s). ¹³C-NMR (126 MHz, CDCl₃) δ ppm: 168.07, 163.40,161.44, 157.82, 151.86, 146.43, 138.81, 138.75, 130.78, 130.75, 129.97,129.90, 125.42, 117.69, 117.52, 113.20, 113.03, 75.81, 58.23, 43.21,40.71, 28.09, 19.32. HRMS [M+H]⁺ calcd for C₁₈H₂₁N₃O₄F: 362.15162.Found: 362.1521.

EXAMPLE 40

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-1-naphthalenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 37. White solid.¹H-NMR (500 MHz, CDCl₃) δ ppm: 12.00 (1H, s), 8.15–8.20 (1H, m), 8.05(1H, d, J=8.2 Hz), 7.73 (1H, br), 7.58–7.65 (2H, m), 7.43 (1H, dd,J=7.8, 5.3 Hz), 7.12 (1H, dd, J=10.1, 7.9 Hz) 5.02 (2H, d, J=6.1 Hz),3.99 (4H, ddd, J=13.8, 8.0, 2.9 Hz), 1.49 (6H, s). ¹³C-NMR (126 MHz,CDCl₃) δ ppm: 168.01, 160.13, 158.12, 157.77, 151.87, 146.51, 132.72,132.68, 128.59, 128.56, 127.86, 126.54, 126.46, 125.42, 124.45, 123.23,121.65, 121.60, 109.00, 108.84, 75.76, 58.21, 43.14, 40.86, 27.99. HRMS[M+H]⁺ calcd for C₂₁H₂₁N₃O₄F: 398.15162. Found: 398.1536.

EXAMPLE 41

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2-methoxyphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(4-fluoro-2-methoxyphenyl)methanamine. HRMS [M+H]⁺ calcd for C₁₈H₂FN₃O₅:378.1465. Found: 378.1480: Light yellow crystals; ¹H NMR (CDCl₃, 500MHz) δ ppm: 1.58 (6H, s, gem-di-Me), 3.88 (3H, s, OMe), 4.00 (4H, s,CH₂), 4.53 (2H, d, J=6.5 Hz, CH₂), 6.61–6.64 (2H, m, Ar—Hs), 7.24 (1H,m, Ar—Hs); ¹³C NMR (CDCl₃, 125.8 Hz) δ ppm: 28.03 (CH₃), 38.79 (CH₂),43.09 (CH₂), 55.72 (CH₃), 58.27 (CH₂), 75.78 (C), 99.15, 99.35 (d, J=27Hz, CH), 106.97, 107.14 (d, J=21 Hz, CH), 121.17, 121.20 (d, J=3.8 Hz,C), 125.75 (C), 130.44, 130.51 (d, J=9.6 Hz, CH), 146.26 (C), 151.50(C), 157.87 (C═O), 158.77, 158.83 (d, J=9.6 Hz, C), 162.63, 164.48 (d,J=234 Hz, CF), 167.81 (C═O); HRMS (ESI) calcd for C₁₈H₂₁FN₃O₅ (M+H)378.1465, Found 378.1480; UV (MeOH) λmax 219 nm (ε 1.66×10⁴), 245 (ε9.69×10³), 305 (ε 7.70×10³); Anal. Calcd for C₁₈H₂₀FN₃O₅.0.2H₂O: C,55.95; H, 5.48; N, 10.88. Found C, 55.99; H, 5.11; N, 10.63.

EXAMPLES 42–43

Examples 42–43 can be prepared from intermediate 31, ethyl9,9-diethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the methods described for examples1, 19 and 20.

EXAMPLE 42

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from 4-fluorobenzylamine. ¹H NMR (500MHz, CDCl₃) δ ppm: 11.96 (1H, br), 7.76 (1H, br), 7.30 (2H, m), 7.06(2H, m), 4.58 (2H, d, J=6.4 Hz), 4.00, (4H, m), 1.93 (2H, m), 1.86 (2H,m), 0.86 (6H, t, J=7.3 Hz). ¹³C NMR (500 MHz, CDCl₃) δ ppm: 168.36,163.46, 157.87, 151.61, 143.23, 133.14, 129.50, 125.58, 115.99, 115.82,80.89, 58.46, 43.13, 42.50, 31.36, 7.79. HRMS [M+H]⁺ calcd forC₁₉H₂₃N₃O₄F: 376.16727. Found: 376.1675.

EXAMPLE 43

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[(4-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-).The title compound can be prepared from 3-methyl, 4-fluorobenzylamine.¹H NMR (500 MHz, CDCl₃) δ ppm: 11.99 (1H, br), 7.74 (1H, br), 7.15–7.09(2H, m), 6.99 (1H, m), 4.54 (2H 6.1 Hz), 4.00, (4H, m), 2.27 (1H, s),1.93 (2H, m), 1.86 (2H, m), 0.84 (6H, t, J=7.3 Hz). ¹³C NMR (126 MHz,CDCl₃) δ ppm: 168.32, 161.97, 160.02, 157.84, 151.56, 146.23, 132.83,130.96, 126.64, 125.59, 115.38, 80.88, 58.48, 43.11, 42.52, 31.36,14.66, 7.79. HRMS [M+H]⁺ calcd for C₂₀H₂₅N₃O₄F: 390.18292. Found:390.1835.

EXAMPLES 44–45

Examples 44–45 can be prepared from intermediate 36,3-hydroxy-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylateand the indicated amines according to the methods described for examples1, 19 and 20.

EXAMPLE 44

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.The title compound can be prepared from 4-fluorobenzylamine ¹H NMR (500MHz, CDCl₃) δ ppm: 11.97 (1H, s), 7.72 (1H, br), 7.31 (1H, d, J=8.5 Hz),7.30 (1H, d, J=8.5 Hz), 7.05 (1H, t, J=8.5 Hz), 4.58 (2H, d, J=6.4 Hz),4.57 (2H, br), 3.67 (2H, t, J=6.4 Hz), 1.95 (2H, p, J=6.1 Hz), 1.57 (6H,s). ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.32, 163.45, 161.49, 158.20,153.63, 147.44, 133.17, 129.50, 129.43, 124.70, 115.97, 115.81, 82.29,60.87, 42.47, 38.68, 27.82, 27.30. HRMS [M+H]⁺ calcd for C₁₈H₂₁N₃O₄F:362.15162. Found: 362.1530.

EXAMPLE 45

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[(4-fluoro-3-methylphenyl)methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.The title compound can be prepared from 3-methyl, 4-fluorobenzylamine.¹H NMR (500 MHz, CDCl₃) δ ppm: 12.00 (1H, s), 7.70 (1H, br), 7.14 (1H,m), 7.1 (1H, m), 6.98 (1H, t, J=8.9 Hz), 4.56 (2H, br), 4.54 (2H, d,J=6.4 Hz), 3.68 (2H, t, J=6.4 Hz), 2.27 (3H, s), 1.95 (2H, p, J=6.1 Hz),1.57 (6H, s). ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.26, 164.98, 160.02,158.22, 153.59, 147.44, 132.82, 130.97, 126.58, 125.46, 124.75, 115.38,82.30, 60.87, 42.51, 38.68, 27.83, 27.31, 14.66. HRMS [M+H]⁺ calcd forC₁₉H₂₃N₃O₄F: 376.16727. Found: 376.1686.

EXAMPLES 46–51

Examples 46–52 can be prepared from the indicated intermediatesaccording to the method provide for example 46.

EXAMPLE 46

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[2-(4-morpholinyl)-2-oxoethoxy]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A solution of intermediate 157,3-benzyloxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-pyrimido[2,1-c][1,4]oxazine-2-carboxylicacid 4-fluoro-2-(2-morpholin-4-yl-2-oxo-ethoxy)-benzylamide, (187 mg,0.32 mmol) in trifluoroacetic acid (2 mL) was stirred at roomtemperature for 2.5 hrs, after which the mixture was concentrated invacuo to dryness. The residual oil was crystallized from 95% ethanol toprovide 120 mg (0.25 mmol, Yield 77%) of the title compound as a whitecrystalline powder: ¹H NMR (CDCl₃, 500 MHz) δ ppm: 1.57 (6H, s, Me),3.51, 3.64 (4H, brs, NCH₂), 3.70 (4H, m, OCH₂), 3.99 (4H, s, NCH₂,OCH₂), 4.60 (2H, d, J=6 Hz, NCH₂), 4.76 (2H, s, OCH₂), 6.59 (1H, dd,J=10, 2.5 Hz, Ar—H), 6.63 (1H, dt, J=2.5, 8 Hz, Ar—H), 7.29 (1H, dd,J=6.5, 8.5 Hz, Ar—H), 8.25 (1H, t, J=6 Hz, NH), 12.2 (br, OH). ¹³C NMR(CDCl₃, 125.77 Hz) δ ppm: 27.93 (CH₃), 38.44 (NCH₂), 42.39 (NCH₂), 43.14(NCH₂), 45.31 (NCH₂), 58.19 (OCH₂), 66.40 (OCH₂), 66.59, 66.86 (OCH₂),75.94 (C), 100.26, 100.46 (d, J=26 Hz, CH), 108.19, 108.36 (d, J=21 Hz,CH), 122.03, 122.06 (d, J=3 Hz, C), 125.84 (C), 131.06, 131.14 (d, J=11Hz, CH), 146.37 (C), 151.46 (C), 157.06, 157.14 (d, J=11 Hz, C), 157.96(C═O), 162.25, 164.21 (d, J=248 Hz, CF), 165.47 (C═O), 168.23 (C═O);HRMS calcd for C₂₃H₂₈N₄O₇F (M+H) 491.1942, Found 491.1958; UV(MeOH))λmax 249 nm (ε 7.84×10³), 290 nm (ε 3.06×10³), 303 nm (ε2.2×10³); Anal. Calcd for C₂₃H₂₇N₄O₇F.1.7H₂O: C, 53.01; H, 5.88; N,10.75. Found C, 52.53; H, 5.37, N, 10.48.

EXAMPLE 47

Benzoic acid,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]-,methyl ester. The title compound can be prepared from intermediate 154,methyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoate.White solid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.94 (1H, br s), 8.76 (1H,t, J=6.77 Hz), 7.69 (1H, dd, J=9.2, 2.9 Hz), 7.53 (1H, dd, J=8.4, 5.5Hz), 7.15–7.22 (1H, m), 4.71 (2H, d, J=7.0 Hz), 3.97 (4H, s), 3.89–3.94(3H, m), 1.56 (6H, s); HRMS (ESI) calcd for C₁₉H₂₀FN₄O₆ (M+H) 406.1414.Found 406.1432.

EXAMPLE 48

Benzoic acid,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]-.The title compound can be prepared from intermediate 190,2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoicacid. White solid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.92 (1H, br s), 8.68(1H, t, J=6.4 Hz), 7.80 (1H, dd, J=8.7, 2.6 Hz), 7.60 (1H, dd, J=8.5,5.5 Hz), 7.30 (1H, dt, J=8.1, 2.8 Hz), 4.78 (2H, d, J=6.7 Hz), 4.00 (4H,s), 1.58 (6H, s); HRMS (ESI) calcd for C₁₈H₁₈FN₃O₆ (M+H) 392.1258. Found392.1250.

EXAMPLE 49

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 143,N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (500 MHz, DMSO-d₆) δ ppm: 11.97 (1H, br s), 9.46 (1H, br s),8.55–8.51 (1H, m), 7.40–7.38 (1H, m), 7.32–7.27 (2H, m), 4.56 (2H, d,J=6.1 Hz), 3.97 (2H, t, J=4.9 Hz), 3.82 (2H, t, J=4.9 Hz), 2.80 (3H, d,J=4.6 Hz), 1.55 (6H, s). HRMS (M+H) calcd for C₁₉H₂₂FN₄O₅: 405.1574.Found: 405.1588.

EXAMPLE 50

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(cyclopropylamino)carbonyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 155,N-(2-(cyclopropylcarbamoyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.White solid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.98 (1H, br s), 8.84 (1H,t, J=7.32 Hz), 7.48 (1H, dd, J=9.0, 5.3 Hz), 7.05–7.16 (2H, m),6.20–6.31 (1H, br s), 4.56 (2H, d, J=6.6 Hz), 3.92–4.02 (4H, m), 2.90(1H, dt, J=7.1, 3.3 Hz), 1.59 (6H, s), 0.88 (2H, q, J=6.6 Hz), 0.57–0.66(2H, m); HRMS (ESI) calcd for C₂₁H₂₃FN₄O₅ (M+H) 431.1731. Found431.1734.

EXAMPLE 51

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[[(2-hydroxyethyl)amino]carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 191,N-(2-((2-aminoethyl)carbamoyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (500 MHz, CDCl₃) δ ppm: 11.98 (1H, br s), 8.88 (1H, t, J=6.0 Hz),7.51 (1H, dd, J=8.2, 5.5 Hz), 7.21 (1H, dd, J=8.5, 2.8 Hz), 7.14 (1H,dt, J=8.3, 2.6 Hz), 6.57–6.63 (1H, m), 4.58 (2H, d, J=6.7 Hz), 4.00 (4H,s), 3.87 (2H, t, J=5.1 Hz), 3.63–3.68 (2H, m), 1.60 (6H, s); HRMS (ESI)calcd for C₂₀H₂₃FN₄O₆ (M+H) 435.1680. Found 435.1700.

EXAMPLE 52

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(4-morpholinylcarbonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 156,N-(4-fluoro-2-(morpholine-4-carbonyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.White solid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.94 (1H, s), 8.46 (1H, t,J=5.5 Hz), 7.47 (1H, dd, J=8.5, 5.5 Hz), 7.10 (1H, dt, J=8.4, 2.4 Hz),6.94 (1H, dd, J=8.2, 2.4 Hz), 4.00 (4H, s), 3.79–3.88 (2H, br), 3.78(2H, br), 3.61 (2H, br), 3.31–3.40 (2H, br), 1.61 (6H, s); HRMS (ESI)calcd for C₂₂H₂₅FN₄O₆ (M+H) 461.1836. Found 461.1852.

EXAMPLE 53–60

Examples 53–60 can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the method described for thesynthesis of examples 1, 19 and 20.

EXAMPLE 53

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1H-imidazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 89. ¹H-NMR (500MHz, CDCl₃) δ ppm: 11.66 (1H, bs), 8.07 (1H, s), 7.74 (1H, t, J=5.5 Hz),7.57 (1H, dd, J=8.7, 5.9 Hz), 7.35 (1H, s), 7.25–7.21 (2H, m), 7.08 (1H,dd, J=8.2, 2.4 Hz), 4.42 (2H, d, J=6.4 Hz), 4.01 (4H, s), 1.59 (6H, s).HRMS [M+H]⁺ calcd for C₂₀H₂₁N₅O₄F: 414.15777. Found: 414.1563. Analcalcd for C₂₀H₂₀N₅O₄F.0.25H₂O: C, 57.48; H, 4.94; N, 16.76; F, 4.55.Found: C, 57.77; H, 4.89; N, 16.29; F, 4.48.

EXAMPLE 54

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[5-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-e.The title compound can be prepared from intermediate 97. ¹H NMR (500MHz, CDCl₃) δ ppm: 11.82 (1H, s), 8.70 (1H, t, J=6.5 Hz), 8.39 (1H, s),8.17 (1H, s), 7.40 (1H, dd, J=8.6, 2.7 Hz), 7.34 (1H, dd, J=8.9, 4.9Hz), 7.17–7.13 (1H, m), 4.44 (2H, d, J=6.7 Hz), 4.01 (4H, s), 1.62 (6H,s). HRMS (M+H) calcd for C₁₉H₂₀FN₆O₄: 415.1530. Found: 415.1544. Analcalcd for C₁₉H₁₉FN₆O₄: C, 55.07; H, 4.62; N, 20.28, F, 4.58. Found: C,54.83; H, 4.51; N, 19.89, F, 4.56.

EXAMPLE 55

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[3-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 93. White solid.36% yield. ¹H-NMR (500 MHz, CDCl₃) δ ppm: 11.96 (1H, s), 8.42–8.39 (2H,m), 7.14–7.11 (1H, m), 4.97 (1H, dd J=14.3, 8.8 Hz), 4.37 (1H, dd,J=14.3, 4.0 Hz), 4.00 (4H, s), 3.86–3.80 (1H, m), 3.75–3.70 (1H, m),3.34–3.24 (2H, m), 2.44–2.39 (2H, m), 2.08–2.00 (1H, m), 1.83–1.77 (1H,m), 1.60 (3H, s), 1.57 (3H, s). HRMS [M+H]⁺ calcd for C₂₁H₂₆N₄O₆FS:481.15572. Found: 481.1559. Anal calcd for C₂₁H₂₅N₄O₆FS: C, 52.49; H,5.24; N, 11.66; S, 6.67; F, 3.95. Found: C, 52.43; H, 5.21; N, 11.61; S,6.56; F, 4.16.

EXAMPLE 56

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[3-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 95. White solid.¹H-NMR (500 MHz, CDCl₃) δ ppm: 11.86 (1H, s), 8.76 (1H, brs), 8.46 (1H,d, J=3.0 Hz), 8.22 (1H, s), 7.48–7.47 (2H, m), 7.29–7.26 (1H, m), 4.44(2H, d, J=6.7 Hz), 4.01 (4H, s), 1.63 (6H, s). HRMS [M+H]⁺ calcd forC₁₉H₂₀N₆O₄F: 415.15302. Found: 415.1541 Anal calcd for C₁₉H₁₉N₆O₄F: C,55.07; H, 4.62; N, 20.28; F, 4.58. Found: C, 55.18; H, 4.42; N, 20.17;F, 4.51.

EXAMPLE 57

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 77. Pale orangesolid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.99 (1H, s), 8.99 (1H, t, J=6.4Hz), 7.91 (2H, s), 7.65–7.58 (2H, m), 7.10 (1H, td, J=8.1, 2.6 Hz), 4.61(2H, d, J=7.0 Hz), 3.97 (4H, s), 1.55 (6H, s). HRMS [M−H]⁻ calcd forC₁₉H₁₈N₆O₄F: 413.13736. Found: 413.1354. Anal calcd for C₁₉H₁₇N₆O₄F: C,55.07; H, 4.62; N, 20.28; F, 4.58. Found: C, 54.94; H, 4.78; N, 20.32;F, 4.53.

EXAMPLE 58

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 77. Pale brownsolid ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.85 (1H, s), 7.88–7.82 (3H, m),7.79 (2H, s), 7.47 (1H, t, J=8.3 Hz), 4.67 (2H, d, J=6.2 Hz), 3.99 (4H,s), 1.56 (6H, s). HRMS [M+H]⁺calcd for C₁₉H₂₀N₆O₄F: 415.15302. Found:415.1513. Anal calcd for C₁₉H₁₉N₆O₄F: C, 55.07; H, 4.62; N, 20.28; F,4.58. Found: C, 54.94; H, 4.76; N, 19.94; F, 4.26.

EXAMPLE 59

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-bromo-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(2-bromo-4-fluorophenyl)methanamine. White needles. ¹H-NMR (300 MHz,CDCl₃) δ ppm: 11.78 (1H, s), 8.08 (1H, t, J=6.0 Hz), 7.39 (1H, dd,J=8.8, 5.8 Hz), 7.31 (1H, dd, J=8.0, 2,6 Hz), 7.01 (1H, dt, J=8.2, 2.6Hz), 4.61 (2H, d, J=6.6 Hz), 3.99 (4H, s), 1.56 (6H, s). HRMS [M+H]⁺calcd for C₁₇H₁₈N₃O₄FBr: 426.04648. Found: 426.0465.

EXAMPLE 60

1H-1,2,4-Triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,methyl este. The title compound can be prepared from intermediate 91.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.90 (1H, s), 8.49 (1H, s),8.36 (1H, t, J=6.2 Hz), 7.72 (1H, dd, J=8.8, 5.9 Hz), 7.26–7.20 (1H, m),7.14 (1H, dd, J=8.4, 2,6 Hz), 4.49 (2H, d, J=6.6 Hz), 4.01 (3H, s), 3.98(4H, s), 1.58 (6H, s). HRMS [M+H]⁺ calcd for C₂₁H₂₂N₆O₆F: 473.1585.Found: 473.1563. Anal calcd for C₂₁H₂₁N₆O₆F.0.5H₂O: C, 52.39; H, 4.61;N, 17.46F, 3.95. Found: C, 52.14; H, 4.70; N, 17.41; F, 4.12.

EXAMPLE 61

1H-1,2,4-Triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-.To a solution of example 60, 1H-1,2,4-triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,methyl ester, (2.156 g, 4.6 mmol) in tetrahydrofuran (200 mL) and water(50 mL) at 0° C. was added lithium hydroxide monohydrate (0.58 g, 13.8mmol). The mixture was stirred at 0° C. 2 h and at room temp for 1 h.The resulting solution was partitioned between ethyl acetate and water.The aqueous phase was acidified with 1 N HCl and extracted with ethylacetate and CH₂Cl₂. The organic extracts were combined, dried (Na₂SO₄)and concentrated to give the title compound as a white solid (2.05 g,97% yield). 1H-NMR (300 MHz, CDCl₃) δ ppm: 11.91 (1H, bs), 8.55 (1H, s),8.43 (1H, t, J=6.6 Hz), 7.77 (1H, dd, J=8.8, 5.9 Hz), 7.28–7.23 (1H, m),7.16 (1H, dd, J=8.0, 2.6 Hz), 4.47 (2H, d, J=6.9 Hz), 3.98 (4H, s), 1.59(6H, s). HRMS [M+H]⁺ calcd for C₂₀H₂₀N₆O₆F: 459.14285. Found: 459.1442.

EXAMPLES 62–72

Examples 62–72 can be prepared from intermediate 61,1H-1,2,4-triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,according to the method described for the synthesis of example 62.

EXAMPLE 62

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-(4-morpholinylcarbonyl)-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To a solution of example 61, 1H-1,2,4-triazole-3-carboxylic acid,1-[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,(0.0259 g, 0.057 mmol) in DMF (2 mL), at 0° C., was addedO-(7-azabenzotriazol-1-yl)-N,N,N¹,N¹-tetramethyluroniumhexafluorophosphate (0.044 g, 0.115 mmol). The solution was stirred at0° C. for 10 min before adding morpholine (0.025 mL, 0.285 mmol) afterwhich it was stirred at room temp for 2 h. Purification by reverse phasepreparative HPLC chromatography (YMC Combiprep ODS-A, 30 mm×50 mm,MeOH/H₂O/0.1% CF₃CO₂H) gave the title compound as a white solid (0.015g, 50% yield). ¹H-NMR (500 MHz, CDCl₃) δ ppm: 8.50 (1H, t, J=6.9 Hz),8.45 (1H, s), 7.69 (1H, dd, J=8.7, 5.9 Hz), 7.22 (1H, td, J=8.2, 2,3Hz), 7.13 (1H, dd, J=8.2, 2.4 Hz), 4.49 (2H, s), 3.98 (4H, s), 3.88–3.72(8H, m), 1.57 (6H, s). HRMS [M+H]⁺ calcd for C₂₄H₂₇N₇O₆F: 528.20069.Found: 528.2025.

EXAMPLE 63

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-[(dimethylamino)carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Pale purple solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.51–8.45 (2H, m),7.70 (1H, dd, J=8.4, 5.9 Hz), 7.24–7.18 (1H, m), 7.12 (1H, dd, J=8.2,2.4 Hz), 4.47 (2H, d, J=6.9 Hz), 3.97 (4H, s), 3.24 (3H, s), 3.15 (3H,s), 1.54 (6H, s). HRMS [M+H]⁺ calcd for C₂₂H₂₅N₇O₅F: 486.19013. Found:486.1887.

EXAMPLE 64

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[[(methylsulfonyl)amino]carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.52 (1H, s), 8.36 (1H, t,J=6.8 Hz), 7.70 (1H, dd, J=8.6, 5.7 Hz), 7.26–7.19 (1H, m), 7.13 (1H,dd, J=8.4, 2.6 Hz), 4.46 (2H, d, J=7.0 Hz), 3.95 (4H, s), 3.39 (4H, s),1.57 (6H, s). HRMS [M+H]⁺ calcd for C₂₁H₂₃N₇O₇FS: 536.1364. Found:536.1376. Anal calcd for C₂₁H₂₂N₇O₇FS.0.07CF₃CO₂H: C, 46.72; H, 4.09; N,18.04; F, 4.23. Found: C, 46.42; H, 3.91; N, 17.70; F, 4.17.

EXAMPLE 65

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-N-[(1R)-2-hydroxy-1-phenylethyl]-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.43 (1H, s), 8.20 (1H, t,J=6.0 Hz), 7.64 (1H, dd, J=8.8, 5.9 Hz), 7.42–7.40 (1H, m), 7.26–7.19(1H, m), 7.11 (1H, dd, J=8.0, 2.6 Hz), 4.53 (2H, d, J=6.6 Hz), 3.99 (4H,s), 3.06 (3H, d, J=4.7 Hz), 1.56 (6H, s). HRMS [M+H]⁺ calcd forC₂₁H₂₃N₇O₅F: 472.1745. Found: 472.1741. Anal calcd for C₂₁H₂₂N₇O₅F: C,53.50; H, 4.70; N, 20.79; F, 4.03. Found: C, 53.22; H, 4.51; N, 20.70;F, 4.01.

EXAMPLE 66

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-[(4-acetyl-1-piperazinyl)carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.46 (1H, s), 8.36 (1H, t,J=5.7 Hz), 7.68 (1H, dd, J=8.6, 5.7 Hz), 7.27–7.21 (1H, m), 7.14 (1H,dd, J=8.2, 2.7 Hz), 4.48 (2H, d, J=6.6 Hz), 3.98 (4H, s), 3.94–3.61 (8H,m), 2.13 (3H, s), 1.55 (6H, s). HRMS [M+H]⁺ calcd for C₂₆H₃₀N₈O₆F:569.2272. Found: 569.2269. Anal calcd for C₂₆H₂₉N₈O₆F.0.8H₂O: C, 53.57;H, 5.29N, 19.22; F, 3.26. Found: C, 53.48; H, 4.95; N, 19.21; F, 3.21.

EXAMPLE 67

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[[(2-hydroxyethyl)methylamino]carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.54 (1H, t, J=7.3 Hz), 8.44(1H, s), 7.66 (1H, dd, J=8.8, 5.8 Hz), 7.21–7.09 (2H, m), 4.44 (2H, d,J=4.4 Hz), 3.93 (4H, s), 3.86–3.78 (2H, m), 3.70–3.65 (2H, m), 3.13 (3H,s), 1.94 (1H, bs), 1.55 (6H, s). HRMS [M+H]⁺ calcd for C₂₃H₂₇N₇O₆F:516.2007. Found: 516.2011. Anal calcd for C₂₃H₂₆N₇O₆F: C, 53.59; H,5.08; N, 19.02; F, 3.68. Found: C, 53.31; H, 5.06; N, 18.80; F, 3.60.

EXAMPLE 68

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[[[(4-fluorophenyl)sulfonyl]amino]carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.47 (1H, s), 8.18–8.13 (2H,m), 7.68 (1H, dd, J=8.8, 5.9 Hz), 7.24–7.16 (3H, m), 7.08 (1H, dd,J=8.0, 2.6 Hz), 4.39 (2H, s), 3.96 (4H, s), 1.55 (6H, s). HRMS [M+H]⁺calcd for C₂₆H₂₄N₇O₇F₂S: 616.1426. Found: 616.1426. Anal calcd forC₂₆H₂₃N₇O₇F₂S: C, 50.73; H, 3.76; N, 15.92; F, 6.17. Found: C, 50.49; H,3.66; N, 15.98; F, 6.12.

EXAMPLE 69

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[(4-methyl-1-piperazinyl)carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Pale brown foam. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.43 (1H, s), 8.29 (1H,t, J=6.8 Hz), 7.63 (1H, dd, J=8.4, 5.9 Hz), 7.25–7.19 (1H, m), 7.11 (1H,dd, J₁=8.0, 2.6 Hz), 4.46 (2H, d, J=6.6 Hz), 3.95 (4H, s), 3.30 bs),2.86 (3H, s), 1.91 (4H, bs), 1.53 (6H, s). HRMS [M+H]⁺ calcd forC₂₅H₃₀N₈O₅F: 541.2323. Found: 541.2341. Anal calcd forC₂₅H₂₉N₈O₅F.0.5CF₃CO₂H.0.5H₂O: C, 46.67; H, 4.41; N, 15.55; F, 14.50.Found: C, 46.86; H, 4.44; N, 15.67; F, 14.48.

EXAMPLE 70

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-[[[2-(dimethylamino)ethyl]amino]carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Pale brown foam. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.39 (1H, s), 7.58 (1H,dd, J=8.6, 5.7 Hz), 7.23–7.14 (1H, m), 7.09 (1H, dd, J=8.4, 2.6 Hz),4.50 (2H, s), 3.95 (4H, s), 3.84 (2H, t, J=5.5 Hz), 3.34 (2H, t, J=6.0Hz), 2.89 (6H, s), 1.55 (6H, s). HRMS [M+H]⁺ calcd for C₂₄H₃₀N₈O₅F:529.2323. Found: 529.2315.

EXAMPLE 71

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-[[[2-(dimethylamino)ethyl]methylamino]carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Pale brown foam. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.44 (1H, s), 8.21 (1H,t, J=6.5 Hz), 7.67–7.58 (1H, m), 7.24–7.09 (2H, m), 4.48–4.45 (2H, m),3.95 (4H, s), 3.94–3.89 (2H, m), 3.37–3.33 (2H, m), 2.91 (6H, s), 2.88(3H, s), 1.56 (6H, s). HRMS [M+H]⁺ calcd for C₂₅H₃₂N₈O₅F: 543.2480.Found: 543.2491. Anal calcd for C₂₅H₃₁N₈O₅F.CF₃CO₂H: C, 45.20; H, 4.32;N, 14.54; F, 17.26. Found: C, 45.13; H, 4.14; N, 14.74; F, 17.01.

EXAMPLE 72

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[[(2-hydroxyethyl)amino]carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.41 (1H, s), 8.32 (1H, t,J=6.2 Hz), 7.63 (1H, dd, J=8.4, 5.9 Hz), 7.20 (1H, dt, J=8.4, 2.6 Hz),7.11 (1H, dd, J=8.4, 2.6 Hz), 4.52–4.50 (2H, m), 3.95 (4H, s), 3.78 (2H,t, J=5.1 Hz), 3.59 (2H, t, J=5.1 Hz), 1.56 (6H, s). HRMS [M+H]⁺ calcdfor C₂₂H₂₅N₇O₆F: 502.1850. Found: 502.1850.

EXAMPLE 73

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2-iodophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 174,N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 4.05 (4H, s, 2×CH₂),4.63 (2H, d, J=7.1 Hz, NCH₂), 7.11 (1H, m, aromatic), 7.42 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 7.62 (1H, dd, J=2.5 Hz and J=8.1 Hz,aromatic), 8.20 (1H, broad t, NH), 11.82 (1H, s, OH). HRMS (ESI⁺)calculated for C₁₇H₁₈FIN₃O₄[M+H⁺]: 474.0326. Found: 474.0328.

EXAMPLES 74–77

Examples 74–77 can be prepared from the indicated intermediates byhydrogenolysis or trifluoroacetic acid mediated hydrolysis.

EXAMPLE 74

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(5-fluoro[1,1′-biphenyl]-2-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 176,N-(4-fluoro-2-phenyl-benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.56 (6H, s, 2×CH₃), 4.03 (4H, s, 2×CH₂),4.56 (2H, d, J=6.0 Hz, NCH₂), 7.03 (1H, dd, J=2.5 Hz and J=9.3 Hz,aromatic), 7.09 (1H, m, aromatic), 7.36 (2H, m, aromatics), 7.42–7.51(5H, m, aromatics and NH), 11.96 (1H, s, OH). HRMS (ESI⁺) calculated forC₂₃H₂₃FN₃O₄ [M+H⁺]: 424.1673. Found: 424.1675.

EXAMPLE 75

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.57 (6H, s, 2×CH₃), 4.04 (4H, s, 2×CH₂),4.55 (2H, d, J=6.1 Hz, NCH₂), 7.04 (1H, dd, J=2.5 Hz and J=9.1 Hz,aromatic), 7.16 (1H, m, aromatic), 7.43 (1H, m, aromatic), 7.49 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 7.52 (1H, broad t, NH), 7.71 (1H, m,aromatic), 8.63 (1H, m, aromatic), 8.70 (1H, m, aromatic), 11.84 (1H, s,OH). HRMS (ESI⁺) calculated for C₂₂H₂₂FN₄O₄ [M+H⁺]: 425.1625. Found:425.1616.

EXAMPLE 76

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-methoxy-3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.Hydrogenolysis of intermediate 175,N-(4-fluoro-2-(2-methoxypyridin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamidegave the title material as a white solid; mp 227° C. ¹HNMR 400 MHz(CDCl₃) δ ppm: 1.58 (6H, s, 2×CH₃), 3.99 (3H, s, OCH₃), 4.04 (4H, s,2×CH₂), 4.43 (2H, broad, NCH₂), 6.97 (1H, dd, J=2.5 Hz and J=8.5 Hz,aromatic), 7.03 (1H, dd, J=5.0 Hz and J=8.5 Hz, aromatic), 7.12 (1H, m,aromatic), 7.45 (1H, dd, J=4.5 Hz and J=8.6 Hz, aromatic), 7.53 (1H, dd,J=2.0 Hz and J=7.1 Hz, aromatic), 7.57 (1H, broad t, NH), 8.28 (1H, dd,J=2.5 Hz and J=5.0 Hz, aromatic), 12.03 (1H, s, OH). HRMS (ESI⁺)calculated for C₂₃H₂₄FN₄O₅ [M+H⁺]: 455.1731. Found: 455.1737.

EXAMPLE 77

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(6-methoxy-3-pyridinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.58 (6H, s, 2×CH₃), 4.02 (3H, s, OCH₃),4.04 (4H, s, 2×CH₂), 4.55 (2H, d, J=6.1 Hz, NCH₂), 6.87 (1H, d, J=9.0Hz, aromatic), 7.01 (1H dd, J=2.0 Hz and J=9.0 Hz, aromatic), 7.12 (1H,m, aromatic), 7.46 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.55 (1H,broad t, NH), 7.60 (1H, dd, J=2.0 Hz and J=8.6 Hz, aromatic), 8.17 (1H,d, J=2.0 Hz, aromatic), 11.89 (1H, s, OH). HRMS (ESI⁺) calculated forC₂₃H₂₄FN₄O₅ [M+H⁺]: 455.1731; Found: 455.1717.

EXAMPLES 78–80

Examples 78–80 can be prepared from the indicated intermediatesaccording to the method described for example 78.

EXAMPLE 78

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1,2-dihydro-2-oxo-3-pyridinyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A solution of intermediate 175,N-(4-fluoro-2-(2-methoxypyridin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.125 g, 0.23 mmol) in acetonitrile (5 ml) was treated with sodiumiodide (0.090 g, 0.6 mmol) and chlorotrimethylsilane (0.45 ml, 3.5mmol), sealed in a pressure resistant vessel and heated at 80° C. for1.5 h. The mixture was diluted with ethyl acetate washed with water andbrine then dried over anhydrous magnesium sulfate. Filtration andremoval of solvent provided the title compound. ¹HNMR 400 MHz (CDCl₃) δppm: 1.60 (6H, s, 2×CH₃), 4.03 (4H, s, 2×CH₂), 4.5 (2H, broad, NCH₂),6.47 (1H, m, aromatic), 6.95 (1H, dd, J=2 Hz and J=9 Hz, aromatic), 7.12(1H, m, aromatic), 7.45 (1H, dd, J=2 Hz and J=7 Hz, aromatic), 7.50 (1H,dd, J=6 Hz and J=9 Hz, aromatic), 7.53 (1H, dd, J=2 Hz and J=7 Hz,aromatic), 8.64 (1H, broad t, NH). HRMS (ESI⁺) calculated forC₂₂H₂₂FN₄O₅ [M+H⁺]: 441.1574. Found: 441.1585.

EXAMPLE 79

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1,6-dihydro-6-oxo-3-pyridinyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-. The title compound can be prepared from example 77. ¹HNMR400 MHz (CDCl₃) δ ppm: 1.59 (6H, s, 2×CH₃), 4.02 (3H, s, OCH₃), 4.05(4H, s, 2×CH₂), 4.55 (2H, d, J=6.6 Hz, NCH₂), 6.95 (1H, d, J=9.0 Hz,aromatic), 7.00 (1H, dd, J=2.6 Hz and J=9.0 Hz, aromatic), 7.17 (1H, m,aromatic), 7.46 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.63 (1H, d,J=2.6 Hz, aromatic), 7.71 (1H, broad t, NH), 7.79 (1H, dd, J=2.6 Hz andJ=9.1 Hz, aromatic). HRMS (ESI⁺) calculated for C₂₂H₂₂FN₄O₅ [M+H⁺];441.1574. Found: 441.1570.

EXAMPLE 80

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1,6-dihydro-6-oxo-2-pyridinyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared fromN-(4-fluoro-2-(6-methoxypyridin-2-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,which can be prepared according to the methods described for thesynthesis of intermediate 175. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.62 (6H,s, 2×CH₃), 4.04 (4H, s, 2×CH₂), 4.60 (2H, d, J=7.0 Hz, NCH₂), 6.38 (1H,d, J=7.0 Hz, aromatic), 6.68 (1H, d, J=9.0 Hz, aromatic), 7.14 (1H, dd,J=2.5 Hz and J=9.1 Hz, aromatic), 7.23 (1H, m, aromatic), 7.50 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 7.58 (1H, dd, J=7.0 Hz and J=9.0 Hz,aromatic), 8.15 (1H, broad t, NH).

EXAMPLES 81–93

Examples 81–93 can be prepared from the indicated intermediates byhydrogenolysis or trifluoroacetic acid mediated hydrolysis.

EXAMPLE 81

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 152,N-(4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide¹HNMR 400 MHz (CDCl₃) δ ppm: 1.64 (6H, s, 2×CH₃), 2.59 (3H, s, CH₃),4.04 (4H, s, 2×CH₂), 4.50 (2H, d J=7.1 Hz, NCH₂), 7.1 (1H, dd, J=2.5 Hzand J=8.6 Hz, aromatic), 7.20 (1H, m, aromatic), 7.72 (1H, dd, J=6.0 Hzand J=8.6 Hz, aromatic), 8.34 (1H, s, CH), 8.80 (1H, broad t, NH), 12.11(1H, s, OH). HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄ [M+H⁺]: 429.1687.Found: 429.1675.

EXAMPLE 82

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.66 (6H, s, 2×CH₃), 2.50 (3H, s, CH₃),4.04 (4H, s, 2×CH₂), 4.32 (2H, d, J=7.0 Hz, NCH₂), 7.05 (1H, dd, J=2.5Hz and J=8.1 Hz, aromatic), 7.27 (1H, m, aromatic), 7.70 (1H, dd, J=6.1Hz and J=8.6 Hz, aromatic), 8.04 (1H, s, CH), 8.61 (1H, broad t, NH),11.90 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄ [M+H⁺]:429.1687. Found: 429.1688.

EXAMPLE 83

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 153,N-(2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.61 (6H, s, 2×CH₃), 2.51 (3H, s, CH₃),4.05 (4H, s, 2×CH₂), 4.72 (2H, d, J=6.6 Hz, NCH₂), 7.44–7.55 (3H, m,aromatics), 7.94 (1H, broad t, NH), 8.46 (1H, s, CH), 11.86 (1H, s, OH).HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄ [M+H⁺]: 429.1687. Found:429.1695.

EXAMPLE 84

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1,2,3-thiadiazol-4-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 172,N-(4-fluoro-2-(1,2,3-thiadiazol-4-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (DMSO-d₆) δ ppm: 1.54 (6H, s, 2×CH₃), 3.83 (2H, broad t,CH₂), 3.96 (2H, broad t, CH₂), 4.61 (2H, d, J=6.7 Hz, NCH₂), 7.39 (1H,m, aromatic), 7.55 (1H, m, aromatic), 7.62 (1H, m, aromatic), 9.41 (1H,broad t, NH), 9.63 (1H, s, CH), 12.0 (1H, s, OH). HRMS (ESI⁺) calculatedfor C₁₉H₁₉FN₅O₄S [M+H⁺]: 432.1142. Found: 432.1124.

EXAMPLE 85

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1H-pyrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 177,N-(4-fluoro-2-(1H-pyrazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.59 (6H, s, 2×CH₃), 4.03 (4H, s, 2×CH₂),4.67 (2H, d, J=6.6 Hz, NCH₂), 6.65 (1H, d, J=2.5 Hz, CH), 7.07 (1H, m,aromatic), 7.31 (1H, dd, J=2.5 Hz and J=9.8 Hz, aromatic), 7.56 (1H, dd,J=5.8 Hz and J=8.3 Hz, aromatic), 7.75 (1H, d, J=2.5 Hz, CH), 9.22 (1H,broad t, NH), 10.33 (1H, broad, NH), 12.2 (1H, s, OH). HRMS (ESI⁺)calculated for C₂₀H₂₁FN₅O₄ [M+H⁺]: 414.1578. Found: 414.1560.

EXAMPLE 86

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(5-methyl-2-oxazolyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 173,N-(4-fluoro-2-(5-methyloxazol-2-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.58 (6H, s, 2×CH₃), 2.48 (3H, s, CH₃),4.01 (4H, s, 2×CH₂), 4.77 (2H, d, J=7.0 Hz, NCH₂), 6.96 (1H, s, CH),7.13 (1H, m, aromatic), 7.61 (1H, dd, J=5.8 Hz and J=8.3 Hz, aromatic),7.70 (1H, dd, J=3.2 Hz and J=9.6 Hz, aromatic), 9.76 (1H, broad t, NH),12.15 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₂FN₄O₅ [M+H⁺]:429.1574; found: 429.1564.

EXAMPLE 87

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(ethylamino)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 170,N-(2-(ethylamino)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.30 (3H, t, J=7.3 Hz, CH₃), 1.59 (6H, s,2×CH₃), 3.12 (2H, m, CH₂), 4.04 (4H, s, 2×CH₂), 4.52 (2H, d, J=6.6 Hz,NCH₂), 5.09 (1H, broad, NH), 6.3–6.37 (2H, m, aromatics), 7.10 (1H, dd,J=6.6 Hz and J=8.1 Hz, aromatic), 7.67 (1H, broad t, NH), 11.93 (1H, s,OH). HRMS (ESI⁺) calculated for C₁₉H₂₄FN₄O₄ [M+H⁺]: 391.1782. Found:391.1774.

EXAMPLE 88

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-ethynyl-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 179,N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.61 (6H, s, 2×CH₃), 3.46 (1H, s, CH), 4.04(4H, s, 2×CH₂), 4.73 (2H, d, J=6.5 Hz, NCH₂), 7.1 (1H, m, aromatic),7.26 (1H, dd, J=2.5 Hz and J=8.5 Hz, aromatic), 7.40 (1H, dd, J=5.6 Hzand J=8.6 Hz, aromatic), 8.18 (1H, broad t, NH), 11.92 (1H, s, OH). HRMS(ESI⁺) calculated for C₁₉H₁₉FN₃O₄ [M+H⁺]: 372.1360. Found: 372.1345.

EXAMPLE 89

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-hydroxy-1-propynyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 182,N-(4-fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.60 (6H, s, 2×CH₃), 4.04 (4H, s, 2×CH₂),4.55 (2H, broad d, CH₂), 4.73 (2H, d, J=6.6 Hz, NCH₂), 7.07 (1H, m,aromatic), 7.20 (1H, dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.38 (1H, dd,J=5.3 Hz and J=8.3 Hz, aromatic), 7.95 (1H, broad t, NH), 11.90 (1H, s,OH). HRMS (ESI⁺) calculated for C₂₀H₂₁FN₃O₅ [M+H⁺]: 402.1465. Found:402.1463.

EXAMPLE 90

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-[(methylsulfonyl)oxy]-1-propynyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 183,3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynylmethanesulfonate. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.62 (6H, s, 2×CH₃), 3.16(3H, s, CH₃), 4.05 (4H, s, 2×CH₂), 4.72 (2H, d, J=6.0 Hz, NCH₂), 5.12(2H, s, OCH₂), 7.12 (1H, m, aromatic), 7.21 (1H, dd, J=2.6 Hz and J=8.6Hz, aromatic), 7.45 (1H, dd, J=5.1 Hz and J=8.6 Hz, aromatic), 8.03 (1H,broad t, NH).

EXAMPLE 91

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[3-(dimethylamino)-1-propynyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 184,N-(2-(3-(dimethylamino)prop-1-ynyl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound was isolated as a trifluoroacetic acid salt. ¹HNMR400 MHz (CDCl₃) δ ppm: 1.62 (6H, s, 2×CH₃), 3.03 (6H, s, 2×CH₃), 4.06(4H, s, 2×CH₂), 4.23 (2H, s, NCH₂), 4.75 (2H, d, J=6.0 Hz, NCH₂), 7.16(1H, m, aromatic), 7.24 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.42(1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.04 (1H, broad t, NH). HRMS(ESI⁺) calculated for C₂₂H₂₆FN₄O₄ [M+H⁺]: 429.1938. Found: 429.1917.

EXAMPLE 92

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-(methylsulfonyl)-1-propynyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 186,N-(4-fluoro-2-(3-(methylsulfonyl)prop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 3.16 (3H, s, SCH₃),4.04 (4H, s, 2×CH₂), 4.17 (2H, s, SCH₂), 4.70 (2H, d, J=6.0 Hz, NCH₂),7.12 (1H, m, aromatic), 7.21 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic),7.49 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.16 (1H, broad t, NH),11.99 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₃FN₃O₆S [M+H⁺]:464.1292. Found: 464.1271.

EXAMPLE 93

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[3-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)-1-propynyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 1.86 (2H, m, CH₂),2.28 (2H, m, CH₂), 3.11 (2H, m, CH₂), 3.53 (2H, m, CH₂), 4.05 (4H, s,2×CH₂), 4.27 (2H, s, NCH₂), 4.73 (2H, d, J=6.0 Hz, NCH₂), 7.07 (1H, m,aromatic), 7.17 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.47 (1H, dd,J=5.6 Hz and J=8.6 Hz, aromatic), 8.12 (1H, broad t, NH).

EXAMPLE 94

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[2-(phenylsulfonyl)ethyl]-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand 7-(aminomethyl)indolin-2-one according to the methods described forexamples 1, 19 and 20. ¹H NMR (500 MHz, DMSO-d₆) δ ppm: 1.58 (s, 6),3.50 (s, 2), 3.83 (m, 2), 3.97 (m, 2), 4.42 (d, 2), 6.9–7.13(overlapping m, 3). Anal calcd C₁₉H₂₀N₄O₅: C, 59.36; H, 5.24; N, 14.57.Found: C, 59.61; H, 5.43; N, 14.46.

EXAMPLE 95

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2-hydroxyphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A solution of intermediate 144,N-(4-fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.070 g, 0.154 mmol) in dichloromethane (3 mL) and trifluoroacetic acid(3 mL) was stirred for 2 hours. The solvent was then removed in vacuoand the resulting residue dissolved in ethyl acetate. The ethyl acetatesolution was washed with 1.0 N HCl (10 mL), dried over sodium sulfate,then filtered. Solvent was removed by rotary evaporator and the crudeproduct purified by reverse phase preparative HPLC, (C18, 30%–40%CH₃CN/H₂O—0.1% CF₃CO₂H). Fractions containing product were concentratedby rotary evaporator and the resulting aqueous suspension extracted withethyl acetate (3×50 mL). The combined organic layers were dried (sodiumsulfate), filtered, and concentrated to dryness by rotary evaporator.The residue was triturated with ether and dried in vacuo to give thetitle compound as a white solid. ¹H NMR (500 MHz, d₆-Acetone) δ ppm:11.96 (2H, s), 9.25 (2H, s), 8.98 (1H, br s), 7.23 (1H, t, J=7.6 Hz),6.63 (1H, dd, J=8.2, 2.4 Hz), 6.57 (1H, dt, J=8.4, 2.4 Hz), 4.53 (2H, d,J=6.7 Hz), 4.05 (2H, d, J=5.2 Hz), 3.90 (2H, t, J=5.2 Hz), 1.55 (6H, s),HRMS [M+H]⁺ calcd for C₁₇H₁₉N₃O₅F: 364.13088. Found: 364.1302.

EXAMPLE 96

Carbamic acid, dimethyl-,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenylester. The title compound can be prepared from intermediate 158,dimethyl-carbamic acid2-{[(3-benzyloxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-pyrimido[2,1-c][1,4]oxazine-2-carbonyl)-amino]-methyl}-5-fluoro-phenylester according to the method described for example 95. Whitecrystalline powder; ¹H NMR (CDCl₃, 500 MHz) δ ppm: 1.56 (6H, s, Me),2.96, 3.11 (2s, NMe), 3.99 (4H, s, CH₂), 4.51 (2H, d, J=6 Hz, NCH₂),6.85 (1H, dd, J=2.5 Hz, 9 Hz, CH), 6.94 (1H, dt, J=2.5 Hz, 8.3 Hz,Ar—H), 7.37 (1H, dd, J=6.5 Hz, 8.5 Hz, Ar—H), 8.05 (1H, brt, J=5 Hz,NH), 12.0 (1H, s, OH); ¹³C NMR (CDCl₃, 125.77 Hz) δ ppm: 27.90 (CH₃),36.68, 36.92 (2s, NCH₃), 37.80 (NCH₂), 43.14 (NCH₂), 58.20 (OCH₂), 75.99(OC), 110.88, 110.07 (d, J=24 Hz, CH), 113.41, 113.57 (d, J=21 Hz, CH),125.71 (C), 125.91, 125.94 (d, J=3.6 Hz, C), 131.57, 131.64 (d, J=9.6Hz, CH), 146.22 (C), 150.83, 150.92 (d, J=11 Hz, C), 151.66 (C), 154.68(C═O), 157.92 (C═O), 161.70, 163.68 (d, J=249 Hz, CF), 167.86 (C═O);HRMS calcd for C₂₀H₂₄N₄O₆F (M+H) 435.1680, found 435.1695 (δ+3.5 ppm).UV (MeOH): λmax 245 nm (ε 1.05×10⁴), 306 nm (ε 8.00×10³); Anal. calcdfor C₂₀H₂₃N₄O₆F; C, 55.30; H, 5.34; N, 12.90. Found C, 55.32; H 5.38; N,12.77.

EXAMPLE 97

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[2-(methylamino)-2-oxoethoxy]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.A solution of intermediate 144,N-(4-fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.150 g, 0.331 mmol) and sodium hydride (0.015 g, 0.37 mmol, 60% oildispersion) in anhydrous dimethylformamide (4 mL) was stirred for 5minutes under a nitrogen atmosphere. The reaction mixture was treatedwith 2-chloro-N-methylacetamide (0.054 g, 0.50 mmol), and stirred for anadditional 16 hours. Solvent was removed by rotary evaporator, and theresulting residue purified by short path flash silica gel chromatography(ethyl acetate). The fractions containing product were combined andconcentrated to dryness. The residue was dissolved in dichloromethane (5mL) and trifluoroacetic acid (5 mL) and stirred for 1 hour. Solvent wasremoved by rotary evaporator and the crude product was triturated with aminimal volume of 95% ethanol. The resulting solid was collected byfiltration, and dried under vacuum resulting in 93 mg (0.21 mmol, Yield65%) of the title compound as a white powder: ¹H NMR (500 MHz, CDCl₃) δppm: 11.92 (1H, s), 7.67 (1H, t, J=6.3 Hz), 7.57 (1H, br), 7.30 (1H, dd,J=8.2, 6.4 Hz), 6.74 (1H, dt, J=8.2, 2.3 Hz), 6.60 (1H, dd, J=10.4, 2.4Hz), 4.68 (2H, d, J=6.7 Hz), 4.45 (2H, s), 4.00 (4H, s), 2.93 (3H, d,J=4.9 Hz), 1.55 (6H, s). ¹³C NMR (125.77 MHz, CDCl₃) δ ppm: 168.05,167.44, 164.79, 162.82, 157.71, 156.57, 156.50, 152.14, 146.60, 131.94,131.86, 125.23, 120.71, 120.68, 108.37, 108.20, 100.76, 100.55, 75.81,67.46, 58.15, 43.24, 38.19, 28.08, 25.83. HRMS [M+H]⁺ calcd forC₂₀H₂₄N₄O₆F: 435.1680. Found: 435.1668.

EXAMPLE 98

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[2-(dimethylamino)-2-oxoethoxy]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 144,N-(4-fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamideaccording to the method described for example 97. White powder; ¹H NMR(500 MHz, CDCl₃) δ ppm: 12.25 (1H, br s), 8.36 (1H, t, J=5.65 Hz), 7.31(1H, dd, J=8.39, 6.56 Hz), 6.67 (1H, dt, J=8.32, 2.29 Hz), 6.57 (1H, dd,J=10.38, 2.14 Hz), 4.76 (2H, s), 4.62 (2H, d, J=6.10 Hz), 4.00 (4H, s),3.06 (3H, s), 3.01 (3H, s), 1.58 (6H, s). ¹³C NMR (125.77 MHz, CDCl₃) δppm: 168.25, 166.62, 164.23, 162.27, 158.02, 157.39, 151.36, 146.39,131.25, 131.18, 125.95, 122.23, 122.20, 108.25, 108.08, 100.47, 100.27,76.03, 66.24, 58.22, 43.15, 38.59, 36.07, 35.77, 27.94. HRMS [M+H]⁺calcd for C₂₁H₂₆N₄O₆F: 449.18365. Found: 449.1837.

EXAMPLE 99

4-Morpholinecarboxylic acid,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenylester. The title compound can be prepared from intermediate 144,N-(4-fluoro-2-hydroxybenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamideaccording to the method described for example 97. White powder; ¹H NMR(500 MHz, CDCl₃) δ ppm: 12.01 (1H, br s), 7.96 (1H, t, J=5.34 Hz), 7.38(1H, dd, J=8.39, 6.26 Hz), 6.97 (1H, dt, J=8.24, 2.44 Hz), 6.87 (1H, dd,J=8.85, 2.44 Hz), 4.51 (2H, d, J=6.10 Hz), 4.00 (4H, s), 3.70–3.76 (4H,m), 3.65–3.70 (2H, m), 3.49–3.54 (2H, m), 1.55 (6H, s). ¹³C NMR (125.77MHz, CDCl₃) δ ppm: 167.91, 163.68, 157.86, 153.48, 151.71, 150.51,150.42, 146.31, 131.58, 131.50, 125.83, 125.59, 113.84, 113.67, 111.03,110.84, 75.93, 66.59, 66.52, 58.22, 45.17, 44.41, 43.16, 37.70, 27.95.HRMS [M+H]⁺ calcd for C₂₂H₂₆N₄O₇F: 477.17856. Found: 477.1788.

EXAMPLE 100

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylthio)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,and (4-fluoro-2-(methylthio)phenyl)methanamine according to the methodsdescribed for the synthesis of examples 1, 19 and 20. White solid. ¹HNMR (300 MHz, CDCl₃) δ ppm: 11.88 (1H, br), 8.03 (1H, t, J=6.04 Hz),7.28 (1H, dd, J=8.42, 5.85 Hz), 6.93 (1H, dd, J=9.51, 2.20 Hz), 6.81(1H, dt, J=8.23, 2.56 Hz), 4.58 (2H, d, J=6.22 Hz), 3.98 (4H, s), 2.49(3H, s), 1.55 (6H, s); HRMS (ESI) calcd for C₁₈H₂₁FN₃O₄S (M+H) 394.1237.Found 394.1218.

EXAMPLE 101

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To a solution of example 100 pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylthio)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-(158 mg, 0.4 mmol), in CH₂Cl₂ (4 mL) was added 3-chloroperoxybenzoicacid (132 mg, 0.6 mmol; 77%, Aldrich) and the mixture stirred at roomtemperature for 2 hrs. After removing the solvent in vacuo, the residuewas triturated with diethyl ether. The crude powder was purified byreverse phase column chromatography (YMC, ODS, 8% CH₃CN/H₂O—0.1%CF₃CO₂H) to provide 32 mg (0.075 mmol, Yield 19%) of the title compoundas a white powder after trituration with diethyl ether, and 35 mg (0.086mmol, Yield 21%) of the corresponding sulfoxide. ¹H NMR (300 MHz, CDCl₃)δ ppm: 11.71 (1H, s), 8.58 (1H, t, J=6.04 Hz), 7.73 (1H, dd, J=8.23,2.74 Hz), 7.68 (1H, dd, J=8.42, 5.12 Hz), 7.32 (1H, dt, J=8.05, 2.93Hz), 4.79 (2H, d, J=6.95 Hz), 3.97 (4H, s), 3.15 (3H, s), 1.56 (6H, s);HRMS (ESI) calcd for C₁₈H₁₉FN₃O₆S (M−H) 424.0979, found 424.0973.

EXAMPLE 102

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylsulfinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo.Formed in the reaction described for example 101. ¹H NMR (300 MHz,CDCl₃) δ ppm: 11.73 (1H, s), 8.19 (1H, t, J=6.59 Hz), 7.54 (1H, dd,J=8.05, 2.93 Hz), 7.47 (1H, dd, J=8.42, 5.12 Hz), 7.16 (1H, dt, J=8.14,2.74 Hz), 4.57–4.81 (2H, m), 3.99 (4H, s), 2.80 (3H, s), 1.56 (6H, s);HRMS (ESI) calcd for C₁₈H₂₁FN₃O₅S (M−H) 410.1196, found 410.1194.

EXAMPLE 103

Pyrimido[2,1-c[ ], 4]oxazine-2-carboxamide,N-[[4-fluoro-2-(S-methylsulfinimidoyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To a solution of example 100, pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(methylthio)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-,(245 mg, 0.75 mmol) in CH₂Cl₂ (3 mL) was added tert-butyl azido formate(115 mg, 0.8 mmol; prepared following the procedure described in OrganicSynthesis 1979, 50, 9–12) and ferrous chloride (FeCl₂, 50 mg) and theresulting mixture stirred for 18 hrs. The mixture was diluted withdichloromethane, washed with water, dried (MgSO₄), filtered andconcentrated to yield 450 mg of3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydro-pyrimido[2,1-c][1,4]oxazine-2-carboxylicacid 4-fluoro-2-(N-tert-butoxycarbonyl-S-methyl)sulfiliminyl-benzylamide as a dark gum; LC/MS m/z 509 (M+H).

A solution of this material, (100 mg) in CF₃CO₂H (1 mL), was stirred for20 min then concentrated. The residue was purified by C-18 reverse phaseHPLC (YMC ODS, 5–10% CH₃CN/H₂O—0.1% CF₃CO₂H) to provide 15 mg (0.037mmol, Yield 21%) of the title compound as the correspondingtrifluoroacetic acid salt. ¹H NMR (300 MHz, DMSO-D6) δ ppm: 11.62 (1H,s), 9.57 (1H, t, J=6.0 Hz), 8.11 (1H, dd, J=8.8, 1.8 Hz), 7.62–7.71 (2H,m), 4.58–4.82 (2H, m), 3.97 (2H, t, J=4.8 Hz), 3.82 (2H, t, J=4.8 Hz),3.37 (3H, s), 1.57 (6H, s); HRMS (ESI) calcd for C₁₈H₂₂FN₄O₄S (M+H)409.1346, found 409.1333.

EXAMPLE 104

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[3-[3-(trifluoromethyl)-3-diaziridinyl]phenyl]methyl]-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand (4-(diaziridin-3-yl)phenyl)methanamine (formed in the preparation ofintermediate 66) according to the methods described for the synthesis ofexamples 1, 19 and 20. White solid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.89(1H, s), 7.81 (1H, t, J=6.0 Hz), 7.52–7.59 (2H, m), 7.38–7.44 (2H, m),4.63 (2H, d, J=6.2 Hz), 4.00 (4H, s) 2.78 (1H, d, J=7.3 Hz), 2.21 (1H,d, J=8.1 Hz), 1.51–1.57 (6H, m); HRMS (ESI) calcd for C₁₉H₂₁F₃N₅O₄ (M+H)440.1546, found 440.1537.

EXAMPLE 105

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[3-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenyl]methyl]-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand intermediate 66,(3-(3-(trifluoromethyl)diaziridin-3-yl)phenyl)methanamine, according tothe methods described for the synthesis of examples 1, 19 and 20. Whitesolid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.86 (1H, s), 7.73–7.84 (1H, m),7.35–7.40 (2H, m), 7.11–7.17 (1H, m, J=2.9 Hz), 7.08–7.11 (1H, m), 4.60(2H, d, J=6.2 Hz), 4.00 (4H, s), 1.55 (6H, s); HRMS (ESI) calcd forC₁₉H₁₉F₃N₅O₄ (M+H) 438.1389, found 438.1371.

EXAMPLE 106

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand intermediate 59,(4-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)methanamine hydrochloride,according to the methods described for the synthesis of examples 1, 19and 20. (white solid); ¹H NMR (300 MHz, CDCl₃) δ ppm: 12.01 (1H, s),9.24 (1H, t, J=6.8 Hz), 7.75 (1H, dd, J=9.5, 2.6 Hz), 7.63 (1H, dd,J=8.4, 5.5 Hz), 7.15 (1H, dt, J=8.2, 2.6 Hz), 4.70 (2H, d, J=7.0 Hz),4.45 (3H, s), 3.96 (4H, s), 1.53 (6H, s); HRMS (ESI) calcd forC₁₉H₂₁FN₇O₄ (M+H) 430.1639, found 430.1649.

EXAMPLE 107

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(1-methyl-1H-tetrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand intermediate 62,(4-fluoro-2-(1-methyl-2H-tetrazol-5-yl)phenyl)methanamine hydrochloride,according to the methods described for the synthesis of examples 1, 19and 20. Off-white solid; ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.83 (1H, s),9.17 (1H, t, J=5.8 Hz), 7.75 (1H, dd, J=8.4, 5.7 Hz), 7.30 (1H, t, J=8.2Hz), 7.14 (1H, d, J=7.9 Hz), 4.43 (2H, d, J=6.7 Hz), 4.14–4.16 (3H, m),4.00 (4H, s), 1.67 (6H, s); HRMS (ESI) calcd for C₁₉H₂₁FN₇O₄ (M+H)430.1639, found 430.1619.

EXAMPLES 108–112

Examples 108–112 can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylateand the indicated amines according to the methods described for thesynthesis of examples 1, 19 and 20.

EXAMPLE 108

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 48,2-(aminomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide. White solid; ¹HNMR (500 MHz, CDCl₃) δ ppm: 11.83 (1H, s), 8.64 (1H, t, J=6.6 Hz), 7.68(1H, dd, J=8.6, 5.5 Hz), 7.50 (1H, dd, J=8.2, 2.8 Hz), 7.26–7.30 (1H,m), 4.80 (2H, d, J=7.0 Hz) 3.99 (4H, s), 2.91 (6H, s), 1.58 (6H, s);HRMS (ESI) calcd for C₁₉H₂₄FN₄O₆S (M+H) 455.1401, found 455.1402.

EXAMPLE 109

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)sulfonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 52,2-(aminomethyl)-5-fluoro-N-methylbenzenesulfonamide hydrochloride.Off-white solid; ¹H NMR (300 MHz, CDCl₃) δ ppm: 11.69 (1H, s), 8.55 (1H,br), 7.58–7.67 (2H, m), 7.24–7.29 (1H, m), 4.87–4.97 (1H, br), 4.82 (2H,d, J=6.2 Hz), 3.97 (4H, s), 2.71 (3H, d, J=4.4 Hz), 1.56 (6H, s); HRMS(ESI) calcd for C₁₈H₂₂FN₄O₆S (M+H) 441.1244. Found 441.1237.

EXAMPLE 110

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(aminosulfonyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 56,2-(aminomethyl)-5-fluorobenzenesulfonamide hydrochloride. Off-whitesolid, ¹H NMR (300 MHz, DMSO-D6) δ ppm: 11.92 (1H, s), 9.33 (1H, t,J=6.4 Hz), 7.66 (1H, dd, J=8.8, 2.2 Hz), 7.41–7.52 (2H, m), 4.89 (2H, d,J=6.2 Hz), 3.98 (2H, t, J=4.9 Hz), 3.83 (2H, t, J=4.9 Hz), 3.37 (2H,br), 1.55 (6H, s); HRMS (ESI) calcd for C₁₇H₂₀FN₄O₆S (M+H) 427.1088,found 427.1082.

EXAMPLE 111

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(1-azetidinylsulfonyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from(2-(azetidin-1-ylsulfonyl)-4-fluorophenyl)methanamine, which wassynthesized according to the methods used to prepare intermediate 48.White solid, ¹H NMR (500 MHz, CDCl₃) δ ppm 11.86 (1H, s), 8.57 (1H, t,J=6.3 Hz), 7.65–7.72 (2H, m), 7.26–7.31 (1H, m), 4.82 (2H, d, J=6.7 Hz),3.99 (4H, s), 3.96 (4H, t, J=7.8 Hz), 2.23–2.32 (2H, m), 1.58 (6H, s);HRMS (ESI) calcd for C₂₀H₂₄FN₄O₆S (M+H) 467.1401, found 467.1398.

EXAMPLE 112

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylthio)phenyl]methyl]-4-oxo-.Prepared according to the method described for the synthesis of example100. White solid, ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.55 (6H, s), 2.50 (3H,s), 3.98 (4H, s), 4.65 (2H, d, J=6.6 Hz), 7.1–7.4 (3H, m), 8.11 (1H, t,J=5.9 Hz), 11.94 (1H, s); LC/MS m/z 376 (M+H).

EXAMPLE 113

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylsulfinyl)phenyl]methyl]-4-oxo-.To a solution example 112, pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylthio)phenyl]methyl]-4-oxo-,(112 mg, 0.3 mmol) in CH₂Cl₂ (5 mL) was added 3-chloroperoxybenzoic acid(69 mg, 0.3 mmol; 77%, Aldrich) and the mixture stirred for 5 min. Afterremoving the solvent in vacuo, the residue was purified by preparativereverse phase HPLC (YMC, ODS, 8–15% CH₃CN/H₂O—0.1% CF₃CO₂H) to provide58 mg (0.16 mmol, Yield 53%) of the title compound as a white powderafter trituration with diethyl ether. ¹H NMR (300 MHz, CDCl₃) δ ppm:1.56 (6H, s), 2.80 (3H, s), 3.98 (4H, s), 4.60–4.94 (2H, m), 7.38–7.61(3H, m) 7.65–7.89 (1H, m), 8.34 (1H, t, J=6.4 Hz), 11.82 (1H, s). HRMS(ESI) calcd for C₁₈H₂₂N₃O₅S (M+H) 392.1280. Found 392.1281.

EXAMPLE 114

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylsufonyl)phenyl]methyl]-4-oxo-.To a solution of example 112, pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylthio)phenyl]methyl]-4-oxo-(112 mg, 0.3 mmol) in CH₂Cl₂ (5 mL) was added 3-chloroperoxybenzoic acid(140 mg, 0.62 mmol; 77%, Aldrich) and the mixture stirred for 20 hrs.After removing the solvent in vacuo, the residue was purified bypreparative reverse phase HPLC (YMC, ODS, 15% CH₃CN/H₂O—0.1% CF₃CO₂H) toprovide 61 mg (0.15 mmol, Yield 50%) of the title compound as a whitepowder after trituration with diethyl ether. ¹H NMR (300 MHz, CDCl₃) δppm: 1.56 (6H, s), 3.14 (3H, s), 3.96 (4H, s), 4.83 (2H, d, J=7.0 Hz),7.39–7.57 (1H, m), 7.60–7.68 (2H, m), 8.02 (1H, d, J=8.4 Hz), 8.65 (1H,t, J=7.0 Hz), 11.78 (1H, brs). HRMS (ESI) calcd for C₁₈H₂₂N₃O₆S (M+H)408.1229. Found 408.1217.

EXAMPLES 115–116

Examples 115–116 can be prepared from the indicated intermediates byhydrogenolysis or trifluoroacetic acid mediated hydrolysis.

EXAMPLE 115

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-thiazolylamino)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 163,N-(4-fluoro-2-(thiazol-2-ylamino)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, DMSO-d6) δ ppm: 11.97 (1H, brs), 9.72 (1H, brs), 9.39(1H, t, J=6.3 Hz), 8.14 (1H, dd, J=2.5, 12.0 Hz), 7.31–7.28 (2H, m),6.99 (1H, d, J=3.8 Hz), 6.84 (1H, ddd(dt), J=2.5, 8.3 Hz), 4.52 (2H, d,J=6.3 Hz), 3.96–3.94 (2H, m), 3.82–3.79 (2H, m), 1.54 (6H, s) LCMS(⁺ESI, M+H⁺) m/z 446. HRMS (ESI⁺) calculated for C₂₀H₂₁FN₅O₄S [M+H⁺]:446.1298. Found: 446.1292.

EXAMPLE 116

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 164,N-(4-fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, DMSO-d6) δ ppm: 11.97 (1H, brs), 9.66 (1H, brs), 9.37(1H, brt, J=6.1 Hz), 7.99 (1H, brd), 7.29 (1H, brt, J=7.1 Hz), 6.88 (1H,ddd(dt), J=2.5, 8.0 Hz), 4.52 (2H, d, J=6.1 Hz), 3.97–3.94 (2H, m),3.82–3.80 (2H, m), 2.55 (3H, s), 1.54 (6H, s); LCMS (⁺ESI, M+H⁺) m/z461. HRMS (ESI⁺) calculated for C₂₀H₂₂FN₆O₄S [M+H⁺]: 461.1407. Found:461.1425.

EXAMPLE 117

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-A solution of intermediate 33, ethyl2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate,(0.208 g, 0.65 mmol) in anhydrous dimethylformamide (2 mL) was stirredwith anhydrous potassium carbonate (0.366 g, 2.6 mmol) at 60° C. for 16hours. This was treated with intermediate 69,(4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride,(0.451 g, 2.08 mmol) and triethylamine (0.5 mL, 3.6 mmol) and stirringcontinued at 100° C. for 16 hours. The solvent was removed by rotaryevaporator and the was purified by preparative reverse phase HPLC (C18,10%–35% CH₃CN/H₂O-0.1% trifluoroacetic acid). Fractions containingproduct were pooled and concentrated by rotary evaporator. The resultingaqueous solution was extracted with ethyl acetate (2×50 mL), and thecombined organic fractions dried (sodium sulfate), filtered, andconcentrated to dryness. The resulting residue was triturated with aminimal volume of 95% ethanol, and the solid collected by filtration togive 103 mg (0.24 mmol, Yield 37%) of the title compound as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.96 (1H, br s), 8.83 (1H, t,J=6.6 Hz), 8.46 (1H, s), 8.17 (1H, s), 7.71 (1H, dd, J=8.5, 6.1 Hz),7.21 (1H, dt, J=8.2, 2.6 Hz), 7.11 (1H, dd, J=8.4, 2.6 Hz), 4.55 (2H,br), 4.44 (2H, d, J=6.7 Hz), 3.67 (2H, t, J=6.4 Hz), 1.91–1.97 (2H, pJ=6.10 Hz), 1.63 (6H, s). ¹³C NMR (125.76 MHz, CDCl₃) δ ppm: 167.97,163.19, 161.20, 158.28, 153.35, 152.90, 147.34, 143.94, 136.89, 134.45,134.37, 128.65, 128.62, 125.01, 117.09, 116.93, 112.42, 112.23, 82.46,60.88, 39.13, 38.56, 27.73, 27.36. HRMS [M+H]⁺ calcd for C₂₀H₂₂N₆O₄F:429.16867. Found: 429.1687. Anal calcd for C₂₀H₂₁N₆O₄F.0.06H₂O: C,55.93; H, 4.96; N, 19.57, F, 4.42. Found: C, 55.80; H, 5.14; N, 19.74,F, 4.46.

EXAMPLE 118

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.The title compound can be prepared from intermediate 148,N-(4-fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamideaccording to the method described for example 46. White powder; ¹H NMR(500 MHz, DMSO-D6) δ ppm: 12.17 (1H, s), 9.23 (1H, t, J=6.4 Hz), 8.56(1H, q, J=4.3 Hz), 7.41 (1H, dd, J=8.6, 5.8 Hz), 7.34 (1H, dd, J=9.2,2.8 Hz), 7.30 (1H, dt, J=8.6, 2.8 Hz), 4.55 (2H, d, J=6.4 Hz), 4.37 (2H,br), 3.64 (2H, t, J=6.4 Hz), 2.80 (3H, d, J=4.6 Hz), 1.80–1.86 (2H, m),1.57 (6H, s); HRMS [M+H]⁺ calcd for C₂₀H₂₃N₄O₅F: 419.17308. Found:419.1713.

EXAMPLE 119

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.The title compound can be prepared from intermediate 31, ethyl9,9-diethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,and intermediate 69,(4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride,according to the methods described for examples 1, 19 and 20. Whitepowder; ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.89 (1H, br s), 8.81 (1H, t,J=6.6 Hz), 8.46 (1H, s), 8.15 (1H, s), 7.69 (1H, dd, J=8.6, 5.8 Hz),7.22 (1H, dt, J=8.2, 2.6 Hz), 7.12 (1H, dd, J=8.4, 2.6 Hz), 4.45 (2H, d,J=6.7 Hz), 3.95–4.02 (4H, m), 1.95–2.03 (2H, m), 1.87–1.96 (2H, m), 0.86(6H, t, J=7.5 Hz). ¹³C NMR (125.76 MHz, CDCl₃) δ ppm: 167.98, 163.19,161.20, 157.88, 152.81, 151.29, 146.05, 143.97, 137.00, 136.93, 134.28,134.21, 128.62, 128.59, 125.85, 117.10, 116.94, 112.58, 112.38, 80.93,58.63, 43.02, 39.20, 31.43, 7.86. HRMS [M+H]⁺ calcd for C₂₁H₂₄N₆O₄F:443.18432. Found: 443.1845.

EXAMPLE 120

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.A solution of intermediate 31, ethyl9,9-diethyl-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,(0.228 g, 0.77 mmol) in anhydrous dimethylformamide (5 mL) was treatedwith anhydrous potassium carbonate (0.279 g, 2.0 mmol) followed bybenzyl bromide (0.145 g, 0.85 mmol), and the mixture stirred for 16hours. The mixture was treated with lithium hydroxide (0.042 g, 1.75mmol) and water (2 mL) and stirred for 20 hours. The reaction mixturewas diluted with water (30 mL) and brought to pH 1 with 6 N hydrochloricacid. The crude product was extracted with ethyl acetate (2×30 mL). Thecombined organic layers were dried (sodium sulfate), filtered, andconcentrated to dryness.

A solution of this material, in anhydrous dimethylformamide (4 mL), wastreated with HATU (0.32 g, 0.83 mmol) and stirred for 10 minutes. Thereaction mixture was treated with intermediate 39,2-aminomethyl-5-fluoro-N-methyl-benzamide trifluoroacetic acid salt,(0.281 g, 0.94 mmol), followed by dimethylaminopyridine, DMAP, (0.140 g,1.125 mmol), and stirred at 60° C. for 3 hours. Solvent was removed byrotary evaporator and the residue purified by flash columnchromatography, eluting with 50% to 60% ethyl acetate in hexanes.Fractions containing the product were pooled and concentrated todryness, which gave a white glassy solid. A sample (approximately 10 mg)was further dried under vacuum, and the remainder used in the followingreaction: ¹H NMR (500 MHz, CDCl₃) δ ppm: 8.47 (1H, t, J=6.2 Hz),7.36–7.45 (3H, m), 7.23–7.27 (2H, m) 7.10 (1H, dd, J=8.8, 2.9 Hz), 7.04(1H, dt, J=8.3, 2.7 Hz), 6.60–6.69 (1H, br), 5.25 (2H, s), 4.50 (2H, d,J=6.2 Hz), 3.94 (4H, s), 2.95 (3H, d, J=5.1 Hz), 1.90–2.02 (5H, m),0.75–0.82 (6H, m).

A solution of the above compound in dichloromethane (5 mL) andtrifluoroacetic acid (5 mL) was stirred for 2 hours. The solvent wasremoved and the crude product was purified by preparative reverse phaseHPLC (C-18 column, 10% to 40% CH₃CN/H₂O—0.1% CF₃CO₂H). Fractionscontaining product were pooled and concentrated in vacuo. The resultingaqueous suspension was extracted with dichloromethane (4×100 mL), andthe combined organic extracts, dried (sodium sulfate), filtered, andconcentrated to dryness. The residue was recrystallized ethanol/H₂O toprovide 0.012 g (0.028 mmol, Yield 4%) of the title compound as a whitesolid. ¹H NMR (500 MHz, DMSO-D6) δ ppm: 12.10 (1H, s), 9.30 (1H, t,J=6.4 Hz), 8.52 (1H, m), 7.39 (1H, dd, J=8.4, 5.7 Hz), 7.26–7.35 (2H,m), 4.57 (2H, d, J=6.4 Hz), 3.94 (2H, t, J=4.9 Hz), 3.84 (2H, t, J=4.9Hz), 2.79 (3H, d, J=4.6 Hz), 1.99–2.09 (2H, m), 1.81–1.91 (2H, m), 0.77(6H, t, J=7.3 Hz). ¹³C NMR (125.76 MHz, DMSO-D6)₈ ppm: 167.86, 167.57,159.65, 156.86, 151.21, 145.10, 137.26, 137.21, 132.52, 130.75, 130.68,125.39, 116.69, 116.52, 114.71, 114.53, 80.04, 57.60, 42.62, 40.05,30.04, 26.03, 7.47. HRMS [M+H]⁺ calcd for C₂₁H₂₆N₄O₅F: 433.18873. Found:433.1872.

EXAMPLES 121–130

Examples 121–130 can be prepared from the indicated intermediatesaccording to the methods described for examples 121 and 122.Alternatively, the examples can be formed by treating the indicatedintermediates with trifluoroacetic acid.

EXAMPLE 121

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-oxo-1-piperidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To intermediate 145,N-(4-fluoro-2-(2-oxopiperidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazin-4(9H)-one, (100 mg, 0.187 mmol) in ethyl acetate (10 mL) was addedpalladium (10% on charcoal) (30 mg). The reaction mixture was stirred at23° C. under a hydrogen atmosphere (balloon) for 3 h. The catalyst wasremoved by filtration on Celite. The filtrate was concentrated in vacuoand the resulting residue triturated with diethyl ether (10 ml) anddried in vacuo to afford 37 mg (45% yield) of the title compound. IR(KBr, cm⁻¹) 3397, 2943, 1636, 1539, 1173. ¹HNMR 400 MHz (MeOD) δ ppm:7.51 (1H, dd, (t), J=7.0 Hz), 7.11 (2H, m), 4.70 (1H, d, J=15.3 Hz),4.24 (1H, d, J=15.3 Hz), 4.05 (2H, m), 3.96 (2H, m,), 3.73 (1H, m), 3.62(1H, m), 2.63–2.48 (2H, m), 2.03 (4H, broad s), 1.62 (6H, s). LCMS(M+H)⁺ m/z 445.

EXAMPLE 122

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-.To intermediate 161,N-(4-fluoro-2-(2-oxopiperidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (100 mg, 0.187 mmol) in ethyl acetate (10 mL) was addedpalladium (10% on charcoal) (30 mg). The reaction mixture was stirred at23° C. under a hydrogen atmosphere (balloon) for 3 h. The catalyst wasremoved by filtration on Celite. The filtrate was concentrated in vacuoand the resulting residue triturated with diethyl ether (10 ml) anddried in vacuo to afford 37 mg (45%) of the title compound. IR (KBr,cm⁻¹) 3397, 2943, 1636, 1539, 1173. ¹HNMR 400 MHz (MeOD) δ ppm: 7.51(1H, dd, (t), J=7.0 Hz), 7.11 (2H, m), 4.70 (1H, d, J=15.3 Hz), 4.24(1H, d, J=15.3 Hz), 4.05 (2H, m), 3.96 (2H, m,), 3.73 (1H, m), 3.62 (1H,m), 2.63–2.48 (2H, m), 2.03 (4H, broad s), 1.62 (6H, s). LCMS (M+H)⁺ m/z445.

EXAMPLE 123

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(2-oxo-1-azetidinyl)phenyl]methyl]-.The title compound can be prepared from intermediate 162,N-(2-(2-oxoazetidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, CDCl₃) δ ppm: 12.15 (1H, brs), 9.65 (1H, brs),7.33–7.20 (4H, m), 4.54 (2H, d, J=6.6 Hz), 3.96–3.94 (2H, m), 3.82–3.79(2H, m), 3.76 (2H, t, J=4.3 Hz), 3.10 (2H, t, J=4.3 Hz), 1.53 (6H, s);LCMS (⁺ESI, M+H⁺) m/z 399.

EXAMPLE 124

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(2-oxo-1-pyrrolidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo.The title compound can be prepared from intermediate 159,N-(4-fluoro-2-(2-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.IR (KBr, cm⁻¹) 3432, 2980, 1689, 1543, 1183. ¹HNMR 400 MHz (MeOD) δ ppm:7.53 (1H, dd, J=9.2, 6.3 Hz), 7.11 (2H, m), 4.52 (2H, s), 4.05 (2H, t,J=5.0 Hz), 3.96 (2H, m), 3.87 (2H, t, J=7.1 Hz), 2.61 (2H, t, J=8.0 Hz),2.26 (2H, m), 1.6 (6H, s). HRMS (ESI⁺) calculated for C₂₁H₂₄FN₄O₅[M+H⁺]: 431.1731. Found: 431.1714.

EXAMPLE 125

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(hexahydro-2-oxo-1H-azepin-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 160,N-(4-fluoro-2-(2-oxoazepan-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2carboxamide. IR (KBr, cm⁻¹) 3392, 2934, 1646, 1522, 1292. ¹HNMR 400 MHz(MeOD) δ ppm: 7.50 (1H, broad s), 7.06 (1H, broad s), 7.01 (1H, d, J=9.0Hz), 4.64 (1H, d, J_(AB)=15.0 Hz), 4.31 (1H, d, J_(AB)=15 Hz), 4.04 (2H,m), 3.96 (3H, m), 3.66 (1H, m), 2.86 (1H, m), 2.65 (1H, m), 2.03 –1.80(6H, m), 1.62 (6H, s), (2H, m). LCMS (M+H)⁺ m/z 459.

EXAMPLE 126

N-(4-Fluoro-2-(2-oxoazetidin-1-yl)benzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 146,N-(4-fluoro-2-(2-oxoazetidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ: 9.46 (d, J=6.4 Hz), 7.34 (1H, dd, J=8.5,6.4 Hz), 7.25 (1H, dd, J=10.2, 2.6 Hz), 7.08 (1H, td, J=8.5, 2.6 Hz),6.90 (1H, m), 4.52 (2H, d, J=6.4 Hz), 3.96 (2H, t, J=5.0 Hz), 3.83–3.77(4H, m), 3.11 (2H, t, J=5.0 Hz), 1.53 (6H, s); LCMS (M+H)⁺ m/z 417.

EXAMPLE 127

N-(4-Fluoro-2-(2-oxooxazolidin-3-yl)benzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared from intermediate 165,N-(4-fluoro-2-(2-oxooxazolidin-3-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.12 (1H, s), 9.34 (1H, t, J=6.2 Hz),7.41 (1H, m), 7.23 (1H, td, J=8.6, 2.5 Hz), 4.48 (4H, m), 4.06 (2H, t,J=7.7 Hz), 3.97 (2H, t, J=5.0 Hz), 3.83 (2H, t, J=5.0 Hz), 1.55 (6H, s).LCMS (M+H)⁺ m/z 433.

EXAMPLE 128

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(2R)-2-(hydroxymethyl)-5-oxo-1-pyrrolidinyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 192,(R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.IR (KBr, cm⁻¹) 3441, 2979, 1684, 1540, 1172. ¹HNMR 400 MHz (MeOD) δ ppm:7.56 (1H, m), 7.15 (2H, m), 4.86–4.31 (3H, m), 4.06 (2H, t, 5.0 Hz),3.98 (2H, t, 5.0 Hz), 3.57 (2H, broad s), 2.72–2.55 (2H, m), 2.41 (1H,m), 2.25 (1H, m), 1.62 (6H, s). LCMS (M+H)⁺ m/z 461.

EXAMPLE 129

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(2R)-2-[(acetyloxy)methyl]-5-oxo-1-pyrrolidinyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 193,(R)-(1-(2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methylacetate. ¹HNMR 400 MHz (MeOD) δ ppm: 7.58 (1H, m), 7.21–7.04 (2H, m),5.24 (2H, s), 4.66–4.21 (3H, m), 4.02–3.92 (5H, m), 2.73 –2.34 (3H, m),2.23–1.61 (5H, m), 1.60 (6H, s). LCMS (M+H)⁺ m/z 503.

EXAMPLE 130

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-[(2S)-2-(hydroxymethyl)-5-oxo-1-pyrrolidinyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 167,(S)-N-(2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (DMSO) δ ppm: 7.36 (1H, m), 7.18 (2H, m), 5.07 (1H, broads), 4.66–4.11 (3H, m), 3.95 (2H, t, 5.1 Hz), 3.80 (2H, t, 5.1 Hz), 3.39(2H, s), 2.43 (1H, m), 2.25 (1H, m), 2.08 (1H, m), 1.51 (6H, s). LCMS(M+H)⁺ m/z 461.

EXAMPLE 131

(R)-N-(2-(2-((Dimethylamino)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 195,(R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.050 g, 0.087 mmol) in MeOH (5 mL) was added Palladium (10%) oncharcoal (0.020 g) and formaldehyde (0.30 mL, 10 mmol). The reactionmixture was stirred at 23° C. under H₂ (balloon) for 5 h. Palladium oncharcoal was then removed by filtration and the solvent was evaporatedin vacuo. The residue was purified by preparative HPLC (YMC-Pack C-18)to afford the title compound (0.013 g, 29% yield): ¹H NMR (400 MHz,MeOD) δppm: 7.56 (1H, dd, J=7.0 Hz), 7.30–7.17 (2H, m), 4.70 (2H, m),4.15 (1H, d, J=15.3 Hz), 4.07 (2H, m), 3.99 (2H, m,), 3.54 (1H, m), 2.93(6H, s), 2.84–2.64 (4H, m), 2.20 (1H, m), 1.65 (6H, s). HRMS calcd forC₂₄H₃₁N₅O₅F: 488.2309. Found 488.2328.

EXAMPLE 132

(R)-N-(2-(2-(Azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution of intermediate 195,(R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0 030 g, 0.052 mmol) in CH₂Cl₂ (1 mL) was added CF₃CO₂H (1 mL) at 23°C. The reaction mixture was stirred at 23° C. for 3 h. Toluene (20 mL)was then added and the solvents evaporated in vacuo. The residue waspurified by preparative HPLC (YMC-Pack C-18) to afford the titlecompound (0.008 g, 31%): ¹H NMR (400 MHz, MeOD) δ ppm: 7.55 (1H, dd,J=6.6 Hz), 7.16 (2H, m), 4.47–4.24 (2H, m), 4.05 (2H, m), 3.98 (2H, m),3.56 (2H, s), 2.70–2.45 (4H, m), 2.11 (1H, m), 1.64 (3H, s), 1.61 (3H,s). HRMS calcd for C₂₂H₂₅N₇O₅F: 486.1901. Found 486.1923.

EXAMPLE 133

(R)-N-(2-(2-(Aminomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.The title compound can be prepared by hydrogenolysis (H₂, 10% Pd—C) ofintermediate 195,(R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹H NMR (400 MHz, MeOD) δ ppm: 7.54 (1H, dd, J=7.0 Hz), 7.25–7.13 (2H,m), 4.62 (2H, m), 4.17 (1H, d, J=15.6 Hz), 4.07 (2H, m), 3.99 (2H, m,),3.23 (2H, d, J=3.1 Hz), 2.79–2.59 (3H, m), 2.14 (1H, m), 1.66 (6H, s).HRMS calcd for C₂₂H₂₇N₅O₅F: 460.1996. Found 460.2014.

EXAMPLES 134–136

Examples 134–136 can be prepared from the indicated intermediates byhydrogenolysis or trifluoroacetic acid mediated hydrolysis.

EXAMPLE 134

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-amino-4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 169,N-(2-amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.IR (KBr, cm⁻¹) 3383, 2979, 1636, 1540, 1288. ¹HNMR 400 MHz (MeOD) δ ppm:7.14 (1H, dd, J=7.3 Hz), 6.44–6–31 (2H, m), 4.69 (1H, broad s), 4.48(2H, broad s), 4.03 (2H, t, J=4.6 Hz), 3.95 (2H, t, J=4.6 Hz), 1.62 (6H,s).

EXAMPLE 135

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(acetylamino)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 189,N-(2-acetamido-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (MeOD) δ ppm: 7.66 (1H, broad d, J=10.5 Hz), 7.40 (1H,broad t, 6.5 Hz), 6.87 (1H, broad t, J=6.5 Hz), 4.55 (2H, m), 4.02 (2H,t, J=5.0 Hz), 3.92 (2H, t, J=5.0 Hz), 2.28 (3H, s), 1.62 (6H, s). HRMS(ESI⁺) calculated for C₁₉H₂₂FN₄O₅ [M+H⁺]: 405.1574. Found: 405.1571.

EXAMPLE 136

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(acetylmethylamino)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 168,N-(4-fluoro-2-(Nmethylacetamido)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.IR (KBr, cm⁻¹) 3407, 2979, 1653, 1539, 1116. ¹HNMR 400 MHz (MeOD) δ ppm:7.53 (1H, m), 7.24–7.06 (2H, m), 4.61–4.45 (2H, m), 4.08 (2H, t, J=5.1Hz), 4.00 (2H, t, J=5.1 Hz), 3.40 (0.6H, s), 3.25 (2.4H, s), 1.85 (2.4H,s), 1.81 (0.6H, s), 1.65 (2.4H, s), 1.64 (2.4H, s), 1.62 (1.2H, s). LCMS(M+H)⁺ m/z 419.

EXAMPLE 137

N-(2-(2,5-Dioxo-2H-pyrrol-1(5H)-yl)benzyl)-3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.To a solution ofN-(2-aminobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0 050 g, 0.114 mmol) in acetic acid (1.5 mL) was added maleic anhydride(0.013 g, 0.131 mmol) and the reaction mixture stirred in a sealed tubeat 115 C for 18 h. Acetic acid was evaporated in vacuo and the residuewas purified by preparative HPLC (YMC-Pack C-18) to afford the titlecompound (0.013 g, 27% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.03 (1H,broad t), 7.59 (1H, m), 7.48 (2H, m), 7.19 (1H, m), 6.92 (2H, s), 4.48(2H, d, J=6.1 Hz), 4.04 (4H, s), 1.62 (6H, s); HRMS calcd forC₂₁H₂₁N₄O₆: 425.1461. Found 425.1451.

EXAMPLE 138

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-(benzo[b]thien-7-ylmethyl)-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To inter-mediate 147,N-(benzo[b]thiophen-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(60 mg, 0.13 mmol) was added CF₃CO₂H (2 mL) at 23° C. The reactionmixture was stirred at 23° C. for 1.5 h. Toluene (20 mL) was then addedand the solvents were evaporated in vacuo. The residue was purified bypreparative HPLC (YMC-Pack C-18) to afford the title compound (0.017 g,34% yield): ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (1H, broad t), 7.86 (1H, d,J=8.0 Hz), 7.51–7.28 (3H, m), 4.93 (2H, d, J=3.9 Hz), 4.05 (4H, s), 1.58(6H, s). HRMS calcd for C₁₉H₂₀N₃O₄S: 386.1175. Found 386.1165.

EXAMPLE 139

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(1,1-dioxidobenzo[b]thien-7-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.To intermediate 196,N-(benzo[b]thiophen-1,1-dione-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide,(0.080 g, 0.16 mmol) was added CF₃CO₂H (2 mL) at 23° C. The reactionmixture was stirred at 23° C. for 2.5 h. Toluene (20 mL) was then addedand the solvents evaporated in vacuo. The residue was purified bycrystallization with MeOH (10 mL) to afford the title compound (0.037 g,55% yield). ¹H NMR (400 MHz, DMSO-d₆) 5:11.87 (1H, s), 9.44 (1H, t,J=6.5 Hz), 7.65 (2H, m), 7.51 (1H, d, J=7.0 Hz), 7.42–7.37 (2H, m), 4.84(2H, d, J=6.2 Hz), 3.99 (2H, t, 5.4 Hz), 3.85 (2H, t, J=5.4 Hz), 1.59(6H, s,). HRMS calcd for C₁₉H₂₀N₃O₆S: 418.1073. Found 418.1078.

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,3-dihydro-1,1-dioxidobenzo[b]thien-7-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound was obtained from intermediate 196,N-(benzo[b]thiophen-1,1-dione-7-ylmethyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamideby reduction, Palladium (10%) on charcoal under H₂. ¹HNMR (400 MHz,CDCl₃) δ: 8.65 (1H, s), 7.58–7.49 (2H, m), 7.32 (1H, d, J=7.0 Hz), 4.86(2H, d, J=6.8 Hz), 3.99 (4H, s), 3.54 (2H, t, J=6.8 Hz), 3.40 (2H, t,J=6.8), 1.61 (6H, s). LCMS (M+H)⁺ m/z 420.

EXAMPLES 141–146

Examples 141–146, listed in Table 9, can be prepared from intermediate25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,according to the methods described for examples 1, 19, and 20. Thecompounds in the table were characterized by LCMS; (Xterra MS-C18,4.6×50 mm); eluted with 10% to 100% B, 4.5 min gradient, (A=H₂O-0.1%CF₃CO₂H, B=CH₃CN-0.1% CF₃CO₂H); flow rate at 2.5 mL/min. WV detection at220 nm). Product retention time (RT, minutes) and molecular weight (MS[M+1]) results are listed in the table.

TABLE 9 Ex- am- ple Structure RT MS 141

1.1 331.17 142

2.07 346.18 143

3.35 376.16 144

2.37 397 145

2.54 388.2 146

3.23 366.15

EXAMPLE 147

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-bromophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 25, ethyl3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,and 2-bromobenzylamine according to the methods described for examples1, 19 and 20. ¹H NMR (300 MHz, DMSO-D6) δ ppm: 1.58 (s, 1), 3.84 (t, 2),3.98 (t, 2), 4.54 (d, 2), 7.25 (m, 2), 7,38 (m, 2), 7.64 (d, 1), 9.43(brm, 1), 12.01 (s, 1).

EXAMPLES 148–200

Examples 148–200, listed in table 10, were synthesized according to thefollowing procedure. To a microwave reaction vessel containing a stirbar, was added Pd(Ph₃P)₄ (30 mg, 25 μmol), followed by anhydrous dioxane(0.5 mL). To this was added example 147,pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-bromophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-,(50 μmol), boronic acid or boronate ester reagent (200 μmol), anhydrousdioxane (0.5 mL) and 2M K₃PO₄ aqueous solution (0.25 mL). The reactionvessel was flushed with nitrogen, capped and heated at 120° C. for 10minutes in a microwave reactor. The reaction mixture was filteredthrough a Whatman 0.45 μm syringe filter and the crude product purifiedusing preparative HPLC (Xterra MS-C18, 30×50 mm); Eluted with 30% to100% B, 8 min gradient, (A=10 mM NH₄OAC (aq.), B=CH₃CN); flow rate at 30mL/min. UV detection at 220 nm) to give the title compound.

The compounds in the table were characterized by LCMS; (Xterra MS-C18,4.6×50 mm); eluted with 10% to 100% B, 4.5 min gradient, (A=H₂O-0.1%CF₃CO₂H, B=CH₃CN-0.1% CF₃CO₂H); flow rate at 2.5 mL/min. UV detection at220 nm). Product retention time (RT, minutes) and observed molecularweight (MS [M+1]) results are listed in the table.

TABLE 10 Example Structure RT MS 148

2.08 457 149

1.91 467.95 150

1.71 407 151

1.98 425.01 152

2.04 437.04 153

2.1 436.97 154

2.41 467.01 155

2.19 486.03 156

2 492.01 157

3.02 454.97 158

1.99 438.04 159

1.66 505.05 160

3.2 406 161

3.36 469.91 162

3.39 419.97 163

3.36 419.97 164

3.14 435.97 165

2.65 421.99 166

2.91 430.99 167

2.93 430.99 168

3.02 491 169

2.11 435.02 170

2.54 476.96 171

2.53 476.96 172

2.66 502.97 173

2.26 448.94 174

2.27 448.94 175

2.36 462.98 176

2.63 498.94 177

3 444.97 178

2.56 462.98 179

3.09 411.98 180

2.66 425.01 181

3.08 450.01 182

2.43 438 183

1.71 410 184

3.02 455 185

3.14 436 186

3.30 478 187

2.76 450.2 188

2.92 442.13 189

2.57 445.15 190

1.34 407.34 191

1.40 421.2 192

2.57 439.36 193

2.84 471.13 194

1.62 457.26 195

1.57 520.31 196

1.57 532.41 197

1.55 457.26 198

2.86 396.2 199

3.08 451.2 200

3.33 396.34

EXAMPLE 201

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluoro-2,5-dibromophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo.A mixture of (2,5-dibromo-4-fluorophenyl)methanamine (1 mmol),intermediate 25 (0.268 g, 1 mmol) and triethylamine (0.5 mL, 3.5 mmol)in ethanol/dimethylformamide (1:1, 3 mL) was heated at 100° C. for 6 h.After cooling, the reaction mixture was purified by preparative HPLC toafford the title compound (0.31 g, 62% yield) as an off-white solid. ¹HNMR (500 MHz, CDCl₃) δ ppm: 11.72 (1H, s), 8.08 (1H, t, J=6.1 Hz), 7.61(1H, d, J=7.0 Hz), 7.38 (1H, d, J=7.6 Hz), 4.61 (2H, d, J=6.4 Hz), 4.02(4H, (4H, s), 1.59 (6H, s).

EXAMPLE 202

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.Off-white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.77 (1H, br s), 8.55(1H, t, J=6.3 Hz), 7.75 (1H, dd, J=8.1, 2.6 Hz), 7.72 (1H, dd, J=8.5,5.2 Hz), 7.34 (1H, td, J=8.0, 2.6 Hz), 4.81 (2H, d, J=6.7 Hz), 4.54 (2H,br), 3.65 (2H, t, J=6.1 Hz), 3.18 (3H, s), 1.93 (2H, m), 1.59 (6H, s);¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.14, 163.14, 161.13, 158.23, 153.73,147.26, 140.77, 140.72, 135.31, 135.25, 132.83, 132.80, 124.83, 121.69121.52, 117.63, 117.43, 82.56, 60.80, 45.14, 40.24, 38.62, 27.76, 27.35.HRMS (ESI) calcd for C₁₉H₂₃N₃O₆FS (M+H): 440.1292. Found: 440.1300.Anal. Calcd for C₁₉H₂₂N₃O₆FS.0.06H₂O: C, 51.80; H, 5.06; N, 9.54, F,4.31; found C 51.83; H, 4.97; N, 9.29, F, 4.12.

EXAMPLE 203

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,9,9-diethyl-N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm: 11.74 (1H, s), 8.54 (1H, t, J=6.6 Hz),7.75 (1H, dd, J=8.2, 2.7 Hz), 7.71 (1H, dd, J=8.5, 5.2 Hz), 7.34 (1H,td, J=8.0, 2.6 Hz), 4.82 (2H, d, J=7.0 Hz), 3.94–4.00 (4H, m), 3.17 (3H,s), 1.93–2.00 (2H, m), 1.84–1.92 (2H, m), 0.83 (6H, t, J=7.3 Hz); ¹³CNMR (126 MHz, CDCl₃) δ ppm: 168.26, 163.13, 161.11, 157.83, 151.66,146.05, 140.69, 140.64, 135.13, 135.07, 132.80, 132.77, 125.63, 121.65,121.48, 117.65, 117.45, 81.03, 58.51, 45.14, 43.08, 40.33, 31.38, 7.87.HRMS (ESI) calcd for C₂₀H₂₅N₃O₆FS (M+H): 454.1448. Found: 454.1448.Anal. calcd for C₂₀H₂₄N₃O₆FS: C, 52.97; H, 5.33; N, 9.27, S 7.07. Found:C, 53.01, H, 5.60, N 9.10, S 7.00.

EXAMPLE 204

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.Pale orange solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.87 (1H, br s), 8.59(1H, t, J=6.4 Hz), 7.69 (1H, dd, J=8.5, 5.2 Hz), 7.49 (1H, dd, J×8.2,2.4 Hz), 7.26 (1H, td, J=7.7, 3.2 Hz), 4.79 (2H, d, J=6.7 Hz), 4.53 (2H,br), 3.65 (2H, t, J=6.1 Hz), 2.90 (6H, s), 1.89–1.96 (2H, m), 1.57–1.61(6H, s); ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.03, 162.71, 160.70, 158.29,153.57, 147.23, 138.51, 138.46, 135.30, 135.25, 132.70, 132.67, 124.99,120.40, 120.24, 116.93, 116.73, 82.59, 60.79, 58.57, 40.26, 38.58,37.59, 27.74, 27.36, 18.55. HRMS (ESI) calcd for C₂₀H₂₆N₄O₆FS (M+H)469.1557; found 469.1557. Anal. calcd for C₂₀H₂₆N₄O₆FS.CH₃CH₂OH: C,51.29; H, 6.07; N, 10.89; S, 6.01; F, 3.69. Found C, 51.29; H, 6.33; N,10.85; S, 6.01; F, 3.54.

EXAMPLE 205

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-9,9-diethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-.White glassy solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 11.85 (1H, br), 8.59(1H, t, J=6.4 Hz), 7.68 (1H, dd, J=8.5, 5.2 Hz), 7.49 (1H, dd, J=8.2,2.4 Hz), 7.24–7.30 (1H, m), 4.80 (2H, d, J=7.0 Hz), 3.94–4.01 (4H, m),2.90 (6H, s), 1.93–2.01 (2H, m), 1.85–1.93 (2H, m), 0.83 (6H, t, J=7.3Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.04, 162.70, 160.70, 158.06,151.44, 145.95, 138.53, 138.49, 135.17, 135.12, 132.62, 132.59, 125.95,120.37, 120.21, 116.87, 116.68, 81.08, 58.51, 43.11, 40.32, 37.58,31.35, 7.87. HRMS (ESI) calcd for C₂₁H₂₈N₄O₆FS (M+H) 483.1714; found483.1702. Anal. calcd for C₂₁H₂₇N₄O₆FS.0.15 CF₃CO₂H: C, 51.20; H, 5.48;N, 11.21; F, 5.51; S, 6.42. Found: C, 51.10; H, 5.23; N, 11.21; F, 5.49;S, 6.32.

EXAMPLE 206

6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-.Off-white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 12.18 (1H, br s),8.14–8.25 (1H, br), 7.41–7.50 (2H, m), 7.31–7.39 (2H, m), 4.96 (1H, ddJ=14.0, 8.9 Hz), 4.54 (2H, br s), 4.44 (1H, dd, J=14.2, 3.2 Hz),3.83–3.92 (1H, m), 3.65 (2H, br), 3.38–3.46 (1H, m), 3.18–3.28 (2H, m),2.32–2.42 (2H, m), 1.89–1.98 (4H, m), 1.55 (6H, d, J=15.9 Hz); ¹³C NMR(126 MHz, CDCl₃) δ ppm: 168.22, 158.38, 153.54, 147.32, 138.80, 137.00,130.88, 129.47, 129.29, 127.68, 125.17, 82.60, 60.74, 54.15, 51.05,39.11, 38.63, 27.76, 27.73, 27.36, 25.04, 24.32. HRMS (ESI) calcd forC₂₂H₂₉N₄O₆S (M+H): 477.1808; found: 477.1794. Anal. calcd forC₂₂H₂₈N₄O₆S.0.5CH₃CH₂OH: C, 55.45; H, 5.92; N, 11.76; S 6.73. Found: C,6.11; N, 11.46; S, 6.48.

EXAMPLE 207

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-diethyl-4-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl].Off-white crystalline solid. ¹H NMR (500 MHz, CDCl₃) δ ppm: 12.11 (1H,br s), 8.20 (1H, br), 7.42–7.48 (2H, m), 7.33–7.40 (2H, m), 4.93 (1H,dd, J=14.2, 8.4 Hz), 4.45 (1H, dd, J=14.2, 3.8 Hz), 3.94–4.02 (4H, m),3.87 (1H, ddd, J=13.0, 9.9, 3.7 Hz), 3.39–3.46 (1H, m), 3.15–3.24 (2H,m), 2.29–2.46 (2H, m), 1.79–2.04 (6H, m), 0.81 (3H, t, J=6.7 Hz), 0.78(3H, t, J=7.3 Hz); ¹³C NMR (126 MHz, CDCl₃) δ ppm: 168.25, 157.91,151.43, 146.14, 139.14, 136.81, 130.79, 129.46, 129.25, 127.90, 125.96,81.15, 58.55, 54.22, 51.09, 43.03, 39.57, 31.21, 25.03, 24.34, 7.82,7.68. HRMS (ESI) calcd for C₂₃H₃₁N₄O₆S (M+H): 491.1964; found: 491.1953.Anal. calcd for C₂₃H₃₀N₄O₆S: C, 56.12; H, 6.48; N, 10.91; S, 6.24.Found: C, 56.14; H, 6.44; N, 11.07; S, 6.05.

EXAMPLE 208

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-[2-(methylthio)ethyl]-4-oxo-.A solution of intermediate 141,N-(4-fluorobenzyl)-3-(benzyloxy)-9-(2-(methylthio)ethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamidein 4 mL CF₃CO₂H was stirred at 60° C. for 1 hr then concentrated. Theresidue was dissolved in CH₂Cl₂ and washed with water then concentrated.Trituration with hexanes gave the title compound as a solid. ¹H NMR (300MHz, CDCl₃) δ ppm: 12.03 (1H, s) 7.75 (1H, m) 6.84–7.40 (4H, m)4.39–4.72 (3H, m) 4.04–4.36 (2H, m) 3.68–3.92 (2H, m) 2.49–2.73 (2H, m)2.07–2.50 (2H, m) 2.02 (3H, s); HRMS (ESI) calcd for C₁₈H₂₀FN₃O₄S (M+H):394.1237, found: 394.1234.

EXAMPLE 209

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-[2-(methylsulfonyl)ethyl]-4-oxo-.A solution of example 208, pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9-[2-(methylthio)ethyl]-4-oxo-,(40 mg, 0.11 mmol) in 2 mL CH₂Cl₂ was treated with excessm-chloroperbenzoic acid (100 mg, 0.4 mmol) and stirred at roomtemperature for 20 hrs. The reaction mixture was washed with water andconcentrated. The crude material was purified by reverse phase HPLC(C18, 12% CH₃CN/H₂O). The fractions containing the product wereconcentrated and lyophilized to afford 5 mg (12% yield) of the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm: 12.10–12.27 (1H, s) 7.80–8.02(1H, m) 7.25–7.39 (2H, m) 6.90–7.09 (2H, m) 4.05–4.72 (5H, m) 3.73–3.99(2H, m) 3.02–3.34 (2 H, m) 2.86–2.91 (3H, s) 2.35–2.78 (2H, m); HRMS(ESI) calcd for C₁₈H₂₀FN₃O₆S (M+H): 426.1135, found: 426.1143.

EXAMPLE 210

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[4-fluoro-2-(3-methyl-5-isoxazolyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 180,N-(4-fluoro-2-(3-methylisoxazol-5-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.59 (6H, s, 2×CH₃), 2.42 (3H, s, CH₃),4.03 (4H, s, 2×CH₂), 4.74 (2H, d, J=6.6 Hz, NCH₂), 6.40 (1H, s,aromatic), 7.18 (1H, m, aromatic), 7.32 (1H, dd, J=2.5 Hz and J=9.1 Hz,aromatic), 7.59 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.29 (1H,broad t, NH), 11.87 (1H, s, OH). HRMS (ESI⁺) calculated for C₂₁H₂₂FN₄O₅[M+H⁺]: 429.1574; found: 429.1584.

EXAMPLE 211

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-[(2Z)-3-amino-1-oxo-2-butenyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.63 (6H, s, 2×CH₃), 2.11 (3H, s, CH₃),4.03 (4H, s, 2×CH₂), 4.58 (2H, d, J=6.5 Hz, NCH₂), 5.38 (1H, broad, NH),5.49 (1H, s, CH), 7.09 (1H, m, aromatic), 7.29 (1H, dd, J=3.0 Hz andJ=9.1 Hz, aromatic), 7.48 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic),9.19 (1H, broad t, NH), 10.26 (1H, broad, NH), 12.21 (1H, s, OH).

EXAMPLE 212

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[[2-(3-bromo-5-isoxazolyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 181,N-(2-(3-bromoisoxazol-5-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (CDCl₃) δ ppm: 1.60 (6H, s, 2×CH₃), 4.03 (4H, s, 2×CH₂),4.74 (2H, d, J=7.1 Hz, NCH₂), 6.63 (1H, s, aromatic), 7.24 (1H, m,aromatic), 7.32 (1H, dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.63 (1H, dd,J=5.5 Hz and J=8.6 Hz, aromatic), 8.20 (1H, broad t, NH), 11.77 (1H, s,OH).

EXAMPLE 213

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,diethyl ester. Hydrogenolysis of intermediate 187, diethyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate(0.089 g, 0.15 mmol) gave 0.065 g (90% yield) of the title compound as awhite solid: mp 124° C. ¹HNMR 400 MHz (CDCl₃) δ ppm: 1.39 (6H, t, J=7.1Hz, 2×CH₃), 1.63 (6H, s, 2×CH₃), 4.02 (4H, s, 2×CH₂), 4.20 (4H, m,2×OCH₂), 4.78 (2H, d, J=6.6 Hz, NCH₂), 7.25 (1H, m, aromatic), 7.49 (1H,m, aromatic), 7.63 (1H, m, aromatic), 9.12 (1H, broad t, NH), 12.1 (1H,broad, OH). HRMS (ESI⁺) calculated for C₂₁H₂₈FN₃O₇P [M+H⁺]: 484.1649;found: 484.1646.

EXAMPLE 214

Pyrimido[2,1-c[1,4]oxazine-2-carboxamide,N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-N-methoxy-9,9-dimethyl-4-oxo-.The title compound can be prepared from intermediate 171,N-(4-fluorobenzyl)-3-(benzyloxy)-N-methoxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.¹HNMR 400 MHz (DMSO-d₆) δ ppm: (mixture of rotamers) 1.52 (6H, s,2×CH₃), 3.59 (3H, s, OCH₃), 3.89 (2H, broad, CH₂), 4.01 (2H, broad,CH₂), 4.68 and 4.91 (2H, broad, NCH₂), 7.18 (2H, m, aromatics), 7.43(2H, m, aromatics), 9.88 and 10.2 (1H, broad, OH).

EXAMPLE 215

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-.The title compound can be prepared from intermediate 101. Pale brownsolid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 12.11 (1H, s), 8.32–8.29 (1H, m),7.46–7.42 (2H, m), 7.36–7.32 (2H, m), 4.92 (1H, dd, J=14.3, 8.8 Hz),4.40 (1H, dd, J=14.1, 3.5 Hz), 3.97 (4H, s), 3.90–3.81 (1H, m),3.47–3.37 (1H, m), 3.24–3.18 (2H, m), 2.42–2.28 (2H, m), 1.97–1.86 (2H,m), 1.54 (3H, s), 1.50 (3H, s). HRMS [M+H]⁺ calcd for C₂₁H₂₇N₄SO₆:463.1651; found: 463.1669. Anal calcd for C₂₁H₂₆N₄SO₆: C, 54.53; H,5.67; N, 12.11; S, 6.93. Found: C, 54.53; H, 5.41; N, 12.40; S, 6.69.

EXAMPLE 216

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-.White solid. ¹H-NMR (300 MHz, CDCl₃) δ ppm: 11.94 (1H, s), 8.86 (1H, t,J=6.2 Hz), 8.42 (1H, s), 8.16 (1H, s), 7.66 (1H, dd, J=7.3, 1.8 Hz),7.51–7.42 (2H, m), 7.35–7.32 (1H, m), 4.45 (2H, d, J=6.6 Hz), 3.98 (4H,s), 1.59 (6H, s). HRMS [M+H]⁺ calcd for C₁₉H₂₁N₆O₄: 397.1624; found:397.1609. Anal calcd for C₁₉H₂₀N₆O₄: C, 57.57; H, 5.08; N, 21.20. Found:C, 57.40; H, 4.96; N, 21.09.

EXAMPLE 217

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-(3-phenylpropyl)- ¹HNMR (500 MHz, DMSO-D6) δ ppm: 1.56 (s, 6H) 1.82–1.89 (m, 2H) 2.62 (t,J=7.48 Hz, 2H) 3.31 (m, 2H) 3.82 (t, J=5.04 Hz, 2H) 3.97 (t, J=5.04 Hz,2H) 7.16–7.24 (m, 3H) 7.29 (m, 2H) 8.91 (s, 1H) 12.41 (s, 1H). Analcalcd for C₁₉H₂₃N₃O₄: C, 63.85; H, 6.48; N, 11.75. Found: C, 63.56; H,6.67; N, 12.01.

EXAMPLES 218–259

Examples 218–259, in table 11, were prepared using methods similar tothose described for examples 1, 19, 20. The compounds were characterizedby LCMS with the observed retention time (RT, minutes) and molecularweight (MS [M+1]) listed in the table.

TABLE 11 Ex- am- ple Structure RT MS 218

1.55 374.2 219

1.60 330.2 220

1.63 348.2 221

1.99 398.16 222

1.61 360.2 223

1.79 344.2 224

1.65 366.2 225

1.27 376.2 226

1.80 364.2 227

2.00 398.2 228

1.97 398.1 229

1.64 390.2 230

1.64 390.24 231

2.01 378.1 232

1.75 390.2 233

1.92 358.2 234

2.01 398.0 235

1.71 390.1 236

1.98 378.1 237

1.95 416.1 238

1.70 366.0 239

1.71 394.0 240

1.80 344.0 241

1.90 416.1 242

1.80 360.1 243

1.90 374.1 244

1.60 360.1 245

1.23 378.1 246

1.99 416.1 247

1.98 376.1 248

1.83 362.1 249

1.77 374.1 250

1.59 372.0 251

1.96 378.1 252

1.50 396.27 253

1.27 415.29 254

1.12 413.31 255

1.05 345.26 256

0.98 345.25 257

0.98 373.29 258

1.44 346.24 259

1.22 346.24

EXAMPLES 260–278

Examples 260–278 were prepared according to the methods used for thepreparation of the compounds in table 3 and characterized by LCMS.

EXAMPLE 260

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(4-morpholinyl)phenyl]methyl]-4-oxo-.LCMS: HPLC retention time=4.03 min, MS=[M+1] 415.23.

EXAMPLE 261

1-Piperazinecarboxylic acid,4-[2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,1,1-dimethylethyl ester. LCMS: HPLC retention time=4.93 min, MS=[M+1]514.24.

EXAMPLE 262

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(1-methylethoxy)phenyl]methyl]-4-oxo-.LCMS: HPLC retention time=4.66 min, MS=[M+1] 388.21.

EXAMPLE 263

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[3-(1-methylethoxy)phenyl]methyl]-4-oxo-.LCMS: HPLC retention time=3.97 min., MS=[M+1] 4388.21.

EXAMPLE 264

Benzoic acid,3-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]-,methyl ester. LCMS: HPLC retention time=3.97 min, MS=[M+1] 388.18.

EXAMPLE 265

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-cyanophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=3.59 min, MS=[M+1] 355.2.

EXAMPLE 266

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3-chloro-2-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.47 min, MS=[M+1] 382.14.

EXAMPLE 267

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,3-dihydro-1,4-benzodioxin-5-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.15 min, MS=[M+1] 388.2.

EXAMPLE 268

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(3,4-dihydro-2H-1,5-benzodioxepin-6-yl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.12 min, MS=[M+1] 402.21.

EXAMPLE 269

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,5-dimethylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.64 min, MS=[M+1] 358.22

EXAMPLE 270

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(5-chloro-2-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.44 min, MS=[M+1] 382.15

EXAMPLE 271

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,4-dichlorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.88 min, MS=[M+1] 398.11.

EXAMPLE 272

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-chloro-2-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.69 min, MS=[M+1] 378.17.

EXAMPLE 273

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-chloro-6-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.39 min, MS=[M+1] 382.13.

EXAMPLE 274

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(6-chloro-2-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.74 min, MS=[M+1] 396.14.

EXAMPLE 275

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,6-difluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.49 min, MS=[M+1] 380.18.

EXAMPLE 276

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2,3-difluoro-4-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.53 min, MS=[M+1] 380.18.

EXAMPLE 277

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(4-chloro-2-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.57 min, MS=[M+1] 382.13.

EXAMPLE 278

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,N-[(2-chloro-6-fluoro-3-methylphenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-.LCMS: HPLC retention time=4.68 min, MS=[M+1] 396.16.

EXAMPLE 279

Pyrimido[2,1-c][1,4]oxazine-2-carboxamide,4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[(]-methyl-1H-indol-4-yl)methyl]-4-oxo-.¹H NMR (500 MHz, DMSO-d₆) δ ppm: 1.56 (s, 6), 3.79 (s, 3), 3.82 (m, 2),3.97 (m, 2), 4.76 (d, 2), 6.62 (d, 1), 6.96 (d, 1), 7.12 (m, 1),7.27–7.38 (overlapping m, 2). HRMS [M+1] calcd for C₂₀H₂₃N₄O₄, 383.1641;found, 383.1717. Anal calcd for C₂₀H₂₂N₄O₄: C, 62.81; H, 5.79; N, 14.65.Found: C, 62.88; H, 6.08; N, 13.56.

EXAMPLE 280

6H-Pyrimido[2,1-c][1,4]oxazepine-2-carboxamide,N-[[4-fluoro-2-(2-oxo-1-azetidinyl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-.¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (1H, s), 9.28 (1H, broad s), 7.37 (1H,dd, J=8.2, 6.7 Hz), 7.23 (1H, dd, J=10.2, 2.4 Hz), 7.04 (1H, m), 4.51(2H, broad s), 4.35 (2H, broad s), 3.79 (2H, t, J=4.4 Hz), 3.62 (2H, m),3.11 (2H, t, J=4.4 Hz), 1.81 (2H, m), 1.55 (6H, s). LCMS (M+H)⁺ m/z 431.

EXAMPLE 281

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,dimethyl ester. Hydrogenation of dimethyl2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate(0.030 g, 0.055 mmol) gave 0.018 g (72%) of the title compound as awhite solid ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.63 (6H, s, 2×CH₃), 3.84(3H, s, OCH₃), 3.87 (3H, s, OCH₃), 4.03 (4H, s, 2×CH₂), 4.77 (2H, d,J=6.5 Hz, NCH₂), 7.28 (1H, m, aromatic), 7.47 (1H, m, aromatic), 7.65(1H, m, aromatic), 9.0 (1H, broad t, NH) 12.0 (1H, broad, OH). MS (ESI+)m/z 456 [M+H⁺].

EXAMPLE 282

Phosphonic acid,[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-,monoethyl ester. The title compound can be prepared from intermediate188, ethyl hydrogen2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate.¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH₃), 1.60 (6H, s,2×CH₃), 4.02 (4H, s, 2×CH₂), 4.12 (2H, m, OCH₂), 4.83 (2H, broad, NCH₂),7.18 (1H, m, aromatic), 7.54 (2H, m, aromatics), 8.49 (1H, broad, NH).HRMS (ESI⁺) calculated for C₁₉H₂₄FN₃O₇P [M+H⁺]: 456.1336; found:456.1353.

1. A compound of Formula I

wherein: R¹ is C₁₋₆(Ar¹)alkyl, C₁₋₆(Ar¹)(CON(R⁸)(R⁹))alkyl,C₁₋₆(Ar¹)(CO₂R¹⁴)alkyl, C₁₋₆(Ar¹)hydroxyalkyl, or C₁₋₆(Ar¹)oxyalkyl; R²is hydrogen, C₁₋₆alkyl, or OR¹⁴; R³ is hydrogen, halo, hydroxy, cyano,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₅₋₇cycloalkenyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁₋₆haloalkoxy, N(R⁸)(R⁹), NHAr², N(R⁶)SO₂R⁷, N(R⁶)COR⁷,N(R⁶)CO₂R⁷, OCOR⁷, OCO₂R⁷, OCON(R⁸)(R⁹), OCH₂CO₂R⁷, OCH₂CON(R⁸)(R⁹),COR⁶, CO₂R⁶, CON(R⁸)(R⁹), SOR⁷, S(═N)R⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), PO(OR⁶)₂,C₂₋₄(R¹²)alkynyl, R¹³, Ar², or Ar³; R⁴ is hydrogen, halo, hydroxy,cyano, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, orN(R⁶)(R⁶); R⁵ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, or N(R⁶)(R⁶); R⁶ is hydrogen, C₁₋₆alkyl,or C₃₋₇cycloalkyl; R⁷ is C₁₋₆alkyl or C₃₋₇cycloalkyl; R⁸ is hydrogen,C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl orC₁₋₆(C₁₋₆dialkylamino)alkyl; R⁹ is hydrogen, C₁₋₆alkyl,C₁₋₆hydroxyalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl or C₁₋₆(C₁₋₆dialkylamino)alkyl;or N(R⁸)(R⁹) taken together is azetidinyl, pyrrolidinyl,(R¹⁰)-piperidinyl, N-(R¹¹)-piperazinyl, morpholinyl, thiomorpholinyl, ordioxothiazinyl; R¹⁰ is hydrogen, C₁₋₆alkyl, or C₁₋₆hydroxyalkyl; R¹¹ ishydrogen, C₁₋₆alkyl, C₃₋₇cyclolkyl, COR⁶, or CO₂R⁶; R¹² is hydrogen,hydroxy, N(R⁶)(R⁶), SO₂R⁷, OSO₂R⁷, or dioxothiazinyl; R¹³ isazetidinonyl, pyrrolidinonyl, valerolactamyl, caprolactamyl, maleimido,oxazolidonyl, or dioxothiazinyl, and is substituted with 0–1substituents selected from the group consisting of hydroxymethyl,acetoxymethyl, and aminomethyl; R¹⁴ is hydrogen or C₁₋₆alkyl;

Ar² is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl,thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, hydroxypyridinyl,quinolinyl, isoquinolinyl, or indolyl, and is substituted with 0–2substituents selected from the group consisting of halo, cyano, benzyl,C₁-alkyl, C₁₋₆alkoxy, N(R⁸)(R⁹), CON(R⁸)(R⁹), CO₂R⁶, CONHSO₂N(R⁶)(R⁶),CONHSO₂N(R⁶)(phenyl), and CONHSO₂N(R⁶)(halophenyl); Ar³ is phenylsubstituted with 0–2 substituents selected from the group consisting ofhalo, cyano, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, (C₁₋₆alkoxy)methyl,C₁₋₆haloalkyl, C₁₋₆haloalkoxy, N(R⁸)(R⁹), CON(R⁶)(R⁶), and CH₂N(R⁸)(R⁹),or is dioxolanylphenyl; and X—Y—Z is C(R¹⁴)₂OC(R¹⁴)₂,C(R¹⁴)₂OC(R¹⁴)₂C(R¹⁴)₂, or C(R¹⁴)₂C(R¹⁴)₂C(R¹⁴)₂C(R¹⁴)₂; or apharmaceutically acceptable salt or solvate thereof.
 2. A compound ofclaim 1 where R¹ is C₁₋₆(Ar¹)alkyl.
 3. A compound of claim 1 where R¹ is


4. A compound of claim 1 where R¹ is


5. A compound of claim 1 where R² is hydrogen.
 6. A compound of claim 1where R³ is hydrogen, halo, N(R⁸)(R⁹), N(R⁶)COR⁷, OCON(R⁸)(R⁹),CON(R⁸)(R⁹), SOR⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), PO(OR⁶)₂, R¹³, or Ar².
 7. Acompound of claim 1 where X—Y—Z is C(R¹⁴)₂OCH₂, C(R¹⁴)₂OCH₂CH₂, orC(R¹⁴)₂OCH₂CH₂CH₂.
 8. A compound of claim 1 where X—Y—Z is CH₂OCH₂,C(CH₃)HOCH₂, C(CH₃)₂OCH₂, CH₂OCH₂CH₂, C(CH₃)HOCH₂CH₂, C(CH₃)₂OCH₂CH₂,CH₂OCH₂CH₂CH₂, C(CH₃)HOCH₂CH₂CH₂, or C(CH₃)₂OCH₂CH₂CH₂.
 9. A compound ofclaim 1 selected from the group consisting ofN-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;9,9-diethyl-N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;9,9-diethyl-N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-9,9-diethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(2-oxo-1-azetidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;9,9-diethyl-N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(2-oxo-1-pyrrolidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;9,9-diethyl-4,6,7,9-tetrahydro-3-hydroxy-4-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(1,2,3-thiadiazol-4-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,7,8,10-tetrahydro-3-hydroxy-10,10-dimethyl-4-oxo-6H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide;N-[[4-fluoro-2-(1-methyl-1H-tetrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(2-oxo-1-piperidinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[(methylamino)sulfonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-(acetylamino)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[3-[(4-methyl-1-piperazinyl)carbonyl]-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(4-morpholinylcarbonyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[[(2-hydroxyethyl)amino]carbonyl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-[3-(4-morpholinylcarbonyl)-1H-1,2,4-triazol-1-yl]phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-N-[[2-(2-oxo-1-azetidinyl)phenyl]methyl]-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(1H-pyrazol-5-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[2-[3-[(dimethylamino)carbonyl]-1H-1,2,4-triazol-1-yl]-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[3-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-N-[[2-(methylsulfonyl)phenyl]methyl]-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N-[[4-fluoro-2-(4-morpholinyl)phenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;N,N-dimethyl-carbamic acid,5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenylester;N-[[2-(aminosulfonyl)-4-fluorophenyl]methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide;and[5-fluoro-2-[[[(4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxopyrimido[2,1-c][1,4]oxazin-2-yl)carbonyl]amino]methyl]phenyl]-phosphonicacid, dimethyl ester; or a pharmaceutically acceptable salt or solvatethereof.
 10. The compound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 11. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 12. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 13. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 14. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 15. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 16. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 17. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 18. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 19. Thecompound of claim 1

or a pharmaceutically acceptable salt or solvate thereof.
 20. Acomposition useful for treating HIV infections comprising a therapeuticamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 21. The composition of claim 20 further comprising atherapeutically effective amount at least one other agent used fortreatment of AIDS or HIV infection selected from the group consisting ofnucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, HIV protease inhibitors, HIV fusioninhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4inhibitors, HIV budding or maturation inhibitors, and HIV integraseinhibitors, and a pharmaceutically acceptable carrier.
 22. Thecomposition of claim 20 wherein the compound of claim 1 isN-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide.23. The composition of claim 22 further comprising a therapeuticallyeffective amount at least one other agent used for treatment of AIDS orHIV infection selected from the group consisting of nucleoside HIVreverse transcriptase inhibitors, non-nucleoside HIV reversetranscriptase inhibitors, HIV protease inhibitors, HIV fusioninhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4inhibitors, HIV budding or maturation inhibitors, and HIV integraseinhibitors, and a pharmaceutically acceptable carrier.
 24. A method fortreating HIV infection comprising administering a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, to a patient in need thereof. 25.The method of claim 24 further comprising administering atherapeutically effective amount of at least one other agent used fortreatment of AIDS or HIV infection selected from the group consisting ofnucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, HIV protease inhibitors, HIV fusioninhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4inhibitors, HIV budding or maturation inhibitors, and HIV integraseinhibitors.
 26. The method of claim 24 wherein the compound of claim 1isN-[(4-fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide.27. The method of claim 26 further comprising a therapeuticallyeffective amount at least one other agent used for treatment of AIDS orHIV infection selected from the group consisting of nucleoside HIVreverse transcriptase inhibitors, non-nucleoside HIV reversetranscriptase inhibitors, HIV protease inhibitors, HIV fusioninhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4inhibitors, HIV budding or maturation inhibitors, and HIV integraseinhibitors, and a pharmaceutically acceptable carrier.